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Molecular dynamics simulation of the hydration of adenosine phosphates
Journal of Molecular Liquids 283 (2019) 359–365
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Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq
Molecular dynamics simulation of the hydration of adenosine phosphates M. Sohrabi-Mahboub a,⁎, S. Jahangiri b, H. Farrokhpour a a b
Department of Chemistry, Isfahan University of Technology (IUT), P.O. Box 84156-83111, Isfahan, Iran Department of Chemistry, Queen's University, 90 Bader Lane, Kingston, ON K7L 3N6, Canada
a r t i c l e
i n f o
Article history: Received 16 November 2018 Received in revised form 7 March 2019 Accepted 16 March 2019 Available online 21 March 2019 Keywords: Adenosine phosphate Hydration Molecular dynamics simulation
a b s t r a c t The hydration behavior of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) has been investigated with molecular dynamics simulations. The spatial distribution of water molecules around different hydration sites of the adenosine phosphates and the average times that water molecules spend in the vicinity of the hydration sites of the phosphate, ribose, and adenine groups have been examined in order to characterize the hydration extent of different regions of the ATP, ADP, and AMP molecules. The water molecules strongly hydrate the negatively-charged phosphate groups of the adenosine phosphates and the interaction between the oxygen and nitrogen atoms of the ribose and adenine rings with water molecules lead to the full hydration of these groups by the water molecules as well. The adenosine phosphates ATP, ADP, and AMP were found to be fully hydrated by the water molecules regardless of the magnitude of their negative charges. Results of this work provide atomic-level information about the hydration of ATP, ADP, and AMP were and are expected to help better understand the behavior of these molecules in biological systems. © 2019 Published by Elsevier B.V.
1. Introduction Adenosine phosphates (AP) are key components of the energy flow in many biological systems. Adenosine-5′-triphosphate (ATP) is a cellular energy carrier which plays a critical role in metabolism [1–3]. One ATP molecule contains a ribose ring connected to one adenine and three phosphate groups [4]. The chemical energy stored in the phosphate bonds is released upon the hydrolysis of ATP which produces adenosine diphosphate (ADP) and one phosphate group [5]. The resulting ADP molecule can also produce a phosphate group and adenosine monophosphate (AMP) which is a building block of ribonucleic acid (RNA) [3]. The hydrolysis process can be reversed by enzymes such as ATP synthase which combine one ADP with a phosphate group to provide one ATP molecule [6,7]. The hydrolysis of ATP depends on the solvation energies of the hydrolysis reaction components and their interaction with the environment including enzyme active sites. Detailed investigation of the hydration behavior of adenosine phosphates provides molecular-level information that might be used to understand the mechanism of the ATP hydrolysis and also helps to understand the hydration behavior of large biomolecules containing adenosine phosphates [8–13]. The terminal phosphate groups of ATP, ADP and AMP are usually deprotonated in
⁎ Corresponding author. E-mail address: [email protected] (M. Sohrabi-Mahboub).
https://doi.org/10.1016/j.molliq.2019.03.085 0167-7322/© 2019 Published by Elsevier B.V.
the aqueous phase and their hydrated negatively charged ions are stable [14]. The hydration of adenosine phosphate series has been investigated with experimental and computational methods. High-resolution microwave dielectric relaxation spectroscopy has been applied to study the hydration properties of adenine nucleotides in aqueous solutions of ATP, ADP, and AMP [15]. It was found that the dielectric properties of the solutions have two Debye components characterized by two distinguished relaxation frequencies [15]. One component has a higher relaxation frequency than that of bulk water and corresponds to hypermobile water while the other has a much lower relaxation frequency compared to that of bulk water and relates to constrained water [15]. This investigation demonstrated the presence of three or four layers of hyper-mobile water around the phosphoryl groups of adenine nucleotides which shows the significant effect of such groups on water structure [15]. The hydration properties of AMP and ATP molecules have also been investigated by means of dielectric spectroscopy in aqueous solution as well as gravimetric studies in solid films [16]. Results of these investigations also confirm the presence of water molecules bound by the solute as well as a large amount of bulk water [16,17]. The balance between the bound and bulk water might affect the metabolic processes that involve adenosine phosphates. The intramolecular conformations of ATP and ADP in aqueous solution have been investigated with high-energy X-ray diffraction. Results revealed that the interaction between the adenine and phosphate groups within the ATP and ADP molecules depends on the experimental conditions such as
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the pH and concentration [18]. Liao et al. investigated the conformational equilibria of ATP in aqueous solutions using molecular dynamics (MD) simulations. The free energies obtained from the simulations showed that Mg2+ ions are attached to the oxygen atoms of the two terminal (end) phosphates or of all three phosphates of ATP [19]. The hydration free energy of deprotonated AMP and ADP in the gas phase has been measured experimentally for clusters containing up to seven water molecules [20]. The experimental results provided evidence for the presence of intramolecular hydrogen bonds and also indicated that the hydration free energies decrease in larger clusters [20]. Electrospray ionization mass spectrometry investigations on the stabilization of the excess charges in singly- and multiply-charged anions of ADP and ATP revealed that the adenine group stabilizes the negatively charged phosphate groups [21]. Theoretical findings also confirm the role of intra-molecular hydrogen bonds as well as solvent molecules in stabilizing the anions in the gas phase [21]. In this work, the hydration of adenosine phosphates is investigated with atomistic molecular dynamics simulation. In particular, the hydration characteristics of various hydration sites on the ribose, adenine and phosphate groups of AMP, ADP, and ATP and also the effect of hydration on the structural features of the anions have been investigated in detail. The theoretical procedure is presented in Section 2. Results are presented and discussed in Section 3 and conclusions are provided in Section 4. 2. Computational details The MD simulations were performed on the deprotonated AMP, ADP, and ATP molecules in 30 × 30 × 30 Å3 cubic boxes containing 800 water molecules. Sodium cations were used as counterions to compensate for the negative charges of AP which are −2, −3 and −4 for AMP, ADP, and ATP, respectively. The CHARMM27 all-atom force field [22,23] was used to describe the AP series and their interaction with Na+ ions and the transferable interaction potential with three points (TIP3P) model [24–26] was used to describe water. The isothermal-isobaric (NPT) ensemble with periodic boundary conditions and minimum-image convention in all three directions were used in all simulations. A cut-off distance of 12.0 Å was used for the van der Waals interactions and the forces were smoothly shifted to zero. The smooth particle mesh Ewald (SPME) [27] algorithm was applied to treat the long-range electrostatic interactions. The simulations were performed at 298 K and 1 atm with Langevin dynamics [28,29] and the Berendsen barostat [30] for keeping the temperature and pressure constant, respectively. The Langevin dynamics damping coefficient was set to of 5 ps−1, the Berendsen pressure relaxation time was set to 100.0 fs and the Berendsen pressure frequency was set to 10 fs. The equations of motion were integrated with the Velocity-Verlet algorithm [31] with a time step 1 fs. All systems were simulated for 2 ns, where the first 0.1 ns was used for equilibration. The MD simulations were performed with the NAMD program [32] and the results were analyzed and visualized using visual molecular dynamics (VMD) program [33]. The packmol program [34] was used to generate the initial simulation cells. The interaction energies (ΔEint) between the adenosine phosphate ions and water molecules were calculated with the self-consistentcharge density functional tight-binding method with third order corrections (DFTB3) [35,36]. The method has been validated and applied for a wide range of ion-water interactions previously [37–39]. The DFTB3 optimizations were performed with the conjugate gradient method with a maximum force tolerance of 1 × 10−5 au. The tolerance for the selfconsistent-charge iterations was set to 1 × 10−5 au. All DFTB3 calculations were performed with the 3ob set of parameters [40] using the DFTB+ code [41]. 3. Results and discussion The hydration behavior of the adenosine phosphate series was investigated by evaluating the spatial distribution of water molecules
around the phosphates, ribose and adenine groups of ATP4−, ADP3−, and AMP2− as well as Na+ ions. The translational mobility of the water molecules around AMP2−, ADP3−, and ATP4− ions was evaluated by calculating the average as well as the maximum time that water molecules of the first hydration shell spend around the ion hydration sites. Furthermore, the orientation of the water molecules around the AP hydration sites was investigated by evaluating the angle between the water dipoles and the vector connecting the hydration sites to the water oxygen atoms. 3.1. Spatial distribution of the water molecules The spatial distribution of the water molecules near different atoms of the AP molecules provides useful insight into the hydration characteristics of the phosphate, ribose and adenine groups. The radial distribution functions (RDF) provides a measure of the probability of finding molecules near a specific target. In this work, the RDF of the water oxygen (Ow) around the phosphorus, oxygen and nitrogen atoms of the adenine phosphate molecules are calculated in order to investigate the local interaction of the water molecules with the phosphate, ribose and adenine groups, respectively. The corresponding RDFs will be referred to as Px-Ow, Ox-Ow, and Nx-Ow, where x represents the atomic labels defined in Fig. 1. The RDFs obtained from the MD simulation trajectories are presented in Figs. 2–4. The RDFs obtained for Pα-Ow, Pβ-Ow, and Pγ-Ow in solutions containing AMP2−, ADP3−, ATP4−, and Na+ ions exhibits a wellpronounced peak around at 3–4 nm corresponding to the first hydration shell of the water molecules. Interestingly, the shape and the position of the RDF obtained for the terminal P groups are similar for all adenosine phosphate systems. In the case of ATP, the first Pβ-Ow and Pγ-Ow peaks are shifted towards higher distances and their height is declined compared to the Pα-Ow peak. This observation means that the middle phosphate groups of ATP have less interaction with the water molecules as they have been partially covered by the ribose or the terminal phosphate groups. The Pα-Ow, Pβ-Ow peaks obtained for ADP have similar heights but the Pβ-Ow peak is slightly shifted towards larger distances, again due to the smaller exposure of the middle phosphate group of ADP to the water molecules. The Pα-Ow RDFs obtained for all adenosine phosphate shows only one significant peak demonstrating the lack of a second hydration shell of the water molecules around the corresponding phosphate groups. The Pβ-Ow and Pγ-Ow RDFs of ADP and ATP have small second shoulders which are very likely due to the first hydration shell of water molecules around the neighboring phosphate groups. These observations clearly indicate the formation of one well-pronounced shell of water molecules around the phosphate groups of the AP without a significant restructuring of water beyond this first shell. The presence of this tight shell of water molecules around the negatively charged phosphate groups in consistent with the results of high-resolution microwave dielectric relaxation spectroscopy which provide experimental evidence for the presence of constrained water around the AP molecules [15]. The Ox-Ow RDFs, which measure the probability of finding water molecules around the oxygen atoms of the ribose rings of AP, are presented in Fig. 3. The RDFs obtained for the oxygen atoms of the OH groups have analogous features and both include one well-defined peak at 3 nm which corresponds to a shell of water molecules hydrogen bonded to the OH groups of the ribose ring. The O4-Ow RDFs also have a small peak around 3 nm due to the presence of water molecules interacting with O4 of the ribose ring although the height of these peaks are much smaller than those obtained for OH groups. Inspection of the simulation trajectories indicates that the OH groups of the ribose ring are hydrogen bond donors to the water molecules while the O4 atom can only accept hydrogen bonds from the water. The hydrogen atoms of the OH groups the ribose ring are more exposed and can easily interact with water molecules while the O4 atom of the ring buried
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Fig. 1. Structure and numbering scheme for adenosine phosphates in deprotonated form.
inside the molecule and can barely form direct hydrogen bonds with the water molecules. The Nx-Ow RDFs obtained for the AP are presented in Fig. 4. All RDFs increase to ~1.1 at distances around 3 nm and slightly fluctuates without showing any significant peak analogous to those observed for the phosphate and ribose OH groups. This observation points to the lack of any significant restructuring of the water molecules around the adenine groups of AMP2−, ADP3−, and ATP4−. However, it should be noted that the N6-Ow RDFs have a slightly more clear peak compared to the other nitrogen atoms which might be due to the formation of stronger
bonds between these atoms and the water molecules. Overall, the RDFs demonstrate that the adenine groups of the AP interact weakly with the water molecules. The binding energies of one water molecule interacting with the N6 atoms of the adenine group are presented in Table 1. The values are −7.0, −7.4, and −6.6 kcal mol−1 for AMP2−, ADP3−, and ATP4−, respectively, which are about two times smaller than the binding energies obtained for the water molecules bound to the oxygen atoms of the phosphate groups (−15.8, −15.6, and −13.6 kcal mol−1 for AMP2−, ADP3−, and ATP4−, respectively) due to the presence of negative charges on the oxygen groups (cf. Table 1).
Fig. 2. RDFs obtained for the phosphorus atoms of AMP2−, ADP3−, and ATP4− and the oxygen atom of water.
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Fig. 3. RDFs obtained for the oxygen atoms of the ribose rings of AMP2−, ADP3−, and ATP4− and the oxygen atom of water.
The smaller binding energies of the N6-water interactions are consistent with the less structured RDFs obtained from the MD simulations. It is also noted that the time that each water molecules spends in the vicinity of the N6 atoms, 2.2–2.3 ps, are also about two times smaller than the corresponding time for the phosphate groups which is 4.4 ps. 3.2. Translational mobility of the water molecules In this section, the average number of water molecules in the first hydration shell (FHS) around the hydration sites of the AMP2−, ADP3−, and ATP4− ions was calculated. Additionally, the average time (τavg) that water molecules spend in FHS, and also the maximum time (τmax) that they stay in FHS were evaluated. The results have been tabulated in Tables 2–4. The average number of water molecules around the terminal phosphate groups of AMP2−, ADP3−, and ATP4− ions are 11, 10, and 7.3, respectively. The average time that these water molecules spend around the terminal phosphate groups are 56.6, 57.1, and 48.2 ps, respectively, while the maximum times that the water molecules spend in the hydration shell are 334, 428, and 488 ps, respectively. According to these results, a smaller number of water molecules hydrate
the terminal oxygen atoms of ATP4− ion, compared to AMP2− and ADP3−, and the average life-time of the water molecules in the hydration shell is shorter than those observed for AMP2− and ADP3−. This observation is consistent with the trend observed for the interaction energy between water and the terminal phosphate groups of the AP which indicates that ΔEint for ATP4−–H2O is ~8 kcal mol−1 smaller than those obtained for AMP2− and ADP3−. The Navg and τavg values obtained for water molecules around the terminal phosphates of AMP2− and ADP3− have similar values which is also consistent with the ion– water interaction energies obtained for these systems. The Navg, τavg, and τmax values obtained for the water molecules in the first hydration shells of the middle phosphate groups of ADP3− and ATP4− are all smaller than their corresponding values obtained for the terminal phosphate group. This is due to the decreased exposure of the middle phosphate groups towards the solvent molecules which prevents the formation of large and tightly-bound hydration shells of water around these phosphate groups. It is noted that the water molecules forming the first hydration shells around the middle phosphate groups of ATP4− have the smallest Navg and τavg values.
Fig. 4. RDFs obtained for the nitrogen atoms of the adenine groups of AMP2−, ADP3−, and ATP4− and the oxygen atom of water.
M. Sohrabi-Mahboub et al. / Journal of Molecular Liquids 283 (2019) 359–365 Table 1 Binding energies of one water molecules around Pα, Pβ, Pγ, atoms, oxygen atoms of ribose ring atoms and N6,7 atoms of adenine group. ΔEint (kcal mol−1)
ATP-series
−15.8 −10.9 −15.6 −7.42 −5.51 −13.6 −7.0 −7.4 −6.6
AMP (Pα-water) ADP (Pβ-water) ADP (Pα-water) ATP (Pγ-water) ATP (Pβ-water) ATP (Pα-water) AMP (N6,7-water) ADP (N6,7-water) ATP (N6,7-water)
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Table 3 Coordination number (CN) of water around oxygen atoms of ribose ring and the average time (τavg) and the maximum time (τmax) that water molecules spend near O2, O3, O4 (the estimated error is ~1 ps and ~5 ps for τavg and τmax, respectively).
AMP (O2-Ow) AMP (O3-Ow) AMP (O4-Ow) ADP (O2-Ow) ADP (O3-Ow) ADP (O4-Ow) ATP (O2-Ow) ATP (O3-Ow) ATP (O4-Ow)
CN
τavg (ps)
τmax (ps)
7.7 7.4 6.6 6.8 6.8 5.3 5.7 6.4 4.9
23.7 22.6 33.4 22.5 22.7 26.7 23.3 23.4 22.6
136.0 124.0 278.0 124.0 134.0 310.0 530.0 214.0 234.0
Comparison of the Navg, τavg, and τmax values obtained for the water molecules around the ribose oxygen atoms reveals that the hydration shell around the O4 atoms of the ribose ring contains a smaller number of water molecules which have shorter τavg and τmax values compared to the hydration shells around the O2 and O3 atoms. This observation is consistent with the RDFs obtained for the water molecules around these hydration sites in all three adenosine phosphate ions. The ΔEint obtained for the O2–water interactions are 4.7, 4.4, and 4.3 kcal mol−1 which are much smaller than the values obtained for the interaction between water and the phosphate groups. It is also noted that the τavg values obtained for the hydration sites of the ribose ring are significantly smaller than those obtained for the phosphate groups reflecting the higher interaction between the water molecules and negativelycharged oxygen atoms of the phosphate groups. The τavg values are also smaller than those of phosphate groups in most cases. The average number of water molecules in the first hydration shells of adenine hydration sites is slightly smaller than those obtained for the ribose ring and the phosphate groups. The τavg and τmax values are generally smaller than those obtained for the ribose and phosphate groups except the values calculated for the N6 and N7 atoms. These two atoms have the most recognizable first hydration shell, according to the RDFs, compared to the other N atoms. The water molecules interacting with the N6 and N7 atoms of the adenine group in all ions, form a very stable structure with these to N atoms. In fact, one water molecule acts as both hydrogen bonds donor and acceptor with respect to the N6 and N7 atoms, respectively. The interaction energies of the water molecule with the N6-N7 site are −7.0, −7.4, and −6.6 kcal mol−1 for AMP2−, ADP3−, and ATP4−, respectively, which are comparable to the values obtained for the terminal phosphate group of ATP4−. Comparison of the average and the maximum time that the water molecules spend various hydration sites of AP is in agreement with the experimental results of high-resolution microwave dielectric relaxation spectroscopy and further confirms the presence of tightly bonded water molecules near the negatively charged phosphate groups.
AMP2− has two peaks which one of them is distributed between 0 and 90° with a maximum of around 45°. The second peak is much smaller and is distributed between 90°–180° with a maximum of around 125°. The first peak corresponds to the water molecules in which hydrogen atoms are oriented towards the phosphate oxygens and the second peaks are very likely due to the interaction of water oxygens with the Na+ atoms. The Pα–Ow dipole distributions in ADP3− and ATP4− also have a large peak between 0 and 90° while their Pβ– Ow and Pγ–Ow dipole distributions have more pronounced second peaks between 90 and 180°. The presence of these distinct peaks with maximum values of around 45° and 125° reveals that the water molecules around the phosphate groups have a rather rigid orientation. The dipole distributions of the water molecules around the O4 ribose hydration sites in all adenosine phosphate ions have a peak between 0 and 90° analogous to the Pα–Ow dipole distributions. The dipole distributions corresponding to the O2 and O3 atoms are almost identical and are broader compared to the O4–Ow dipole distributions. The broader peaks of the O2,3–Ow distributions can be related to the higher freedom of the water molecules around these atoms compared to the O4 hydration site. The N–Ow dipole distributions have very broad peaks between 0 and 180° again because of the higher freedom of the water molecules around these hydration sites. The broad peaks around the adenosine hydration sites are consistent with the broad RDFs obtained for these systems which are related to the presence of less structured water molecules around these hydration sites. The difference in the hydration extent of different regions of the AP anions, as reflected in the RDFs, residential times and orientational dynamics of the water molecules around various hydration sites of APs, is expected to affect the interaction of AP anions with other biological molecules. The less hydrated adenosine residues might better interact with hydrophobic regions of larger biomolecules and show higher affinity towards interfacial region
3.3. Orientational dynamics of the water molecules
Table 4 Coordination number (CN) of water around nitrogen atoms of adenine and the average time (τavg) and the maximum time (τmax) that water molecules spend near N1, N3, N6, N7, N9 (the estimated error is ~1 ps and ~5 ps for τavg and τmax, respectively).
The distribution of the angles between the vector that connects the water oxygens to the center of the hydrated sites and the water dipole vectors are plotted in Figs. 5–7. The Pα–Ow dipole distribution in Table 2 Coordination number (CN) of water around Pα, Pβ, Pγ, atoms and the average time (τavg) and the maximum time (τmax) that water molecules spend near Pα, Pβ, Pγ (the estimated error is ~1 ps and ~5 ps for τavg and τmax, respectively). CN AMP (Pα-Ow) ADP (Pβ-Ow) ADP (Pα-Ow) ATP (Pγ-Ow) ATP (Pβ-Ow) ATP (Pα-Ow)
11.0 10.0 7.9 7.3 6.7 6.9
τavg (ps)
τmax (ps)
56.6 57.1 43.9 48.2 35.9 35.0
334.0 428.0 328.0 488.0 378.0 278.0
AMP (N1-Ow) AMP (N3-Ow) AMP (N6-Ow) AMP (N7-Ow) AMP (N9-Ow) ADP (N1-Ow) ADP (N3-Ow) ADP (N6-Ow) ADP (N7-Ow) ADP (N9-Ow) ATP (N1-Ow) ATP (N3-Ow) ATP (N6-Ow) ATP (N7-Ow) ATP (N9-Ow)
CN
τavg (ps)
τmax (ps)
6.9 6.8 8.7 7.6 5.4 6.0 6.2 7.1 6.4 4.9 6.1 5.9 7.8 6.7 4.7
20.2 20.8 25.8 25.7 19.2 18.8 20.6 22.9 23.9 18.8 18.8 19.2 23.9 25.8 19.4
134 164 170 202 150 156 190 134 226 274 120 262 146 442 452
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Fig. 5. Distribution of the angle between the water dipoles and the vector connecting the hydration sites of AMP2− to the water oxygen atoms.
as observed for other classes of organic ions [42] and also anions of the Hofmeister series [43,44]. The presence of differently hydrated regions might also lead to the aggregation of AP anions in aqueous solutions. 4. Conclusions Molecular dynamics simulations have been performed to investigate the hydration behavior of AP including ATP, ADP, and AMP. The radial distribution functions of the water molecules in the vicinity of the phosphate groups have well-defined peaks as a result of the strong interaction between the water hydrogens and the negatively-charged oxygen atoms of the phosphate groups of the AP. The water radial distribution functions obtained for the ribose and adenine groups have much smaller peaks compared to those obtained for the phosphate groups. The average time that water molecules stay in the first hydration shell of the phosphate groups were found to be 1.5–2 times larger than those obtained for the ribose and adenine groups which is consistent with strong interactions of the water molecules with the phosphate
groups of AP. The orientation of the water molecules around different regions of the AP also confirm that water molecules are more tightly bound to the phosphate groups. According to these observations, it is concluded that the phosphate groups of AMP, ADP, and ATP are more tightly wrapped by distinct shells of water molecules while the ribose and adenine groups are loosely surrounded by the water molecules. However, despite the localization of the negative charges on the phosphate groups, the presence of multiple hydration sites on the ribose and adenine rings make the whole molecules to be fully hydrated. Furthermore, the strong interactions between the oxygen atoms of the phosphate groups and water molecules lead to the formation of more structured networks of water around the phosphate groups. Further investigations of the difference in the hydration extents of different regions of AP will provide more insight into the hydration behavior of these important molecules at interfaces. Nomenclature ATP adenosine-5′-triphosphate
Fig. 6. Distribution of the angle between the water dipoles and the vector connecting the hydration sites of ADP3− to the water oxygen atoms.
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Fig. 7. Distribution of the angle between the water dipoles and the vector connecting the hydration sites of ATP4− to the water oxygen atoms.
ADP AMP RNA AP FHS MD TIP3P
adenosine-5′-diphosphate adenosine-5′-monophosphate ribonucleic acid adenosine phosphates first hydration shell molecular dynamics transferable interaction potential with three points water model CHARMM Chemistry at HARvard Molecular Mechanics NPT isothermal-isobaric statistical mechanical ensemble PME particle mesh Ewald VMD visual molecular dynamics DFTB3 density functional tight-binding method with third order corrections RDF radial distribution functions Ow oxygen of water Hw hydrogen of water
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Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq
Molecular dynamics simulation of the hydration of adenosine phosphates M. Sohrabi-Mahboub a,⁎, S. Jahangiri b, H. Farrokhpour a a b
Department of Chemistry, Isfahan University of Technology (IUT), P.O. Box 84156-83111, Isfahan, Iran Department of Chemistry, Queen's University, 90 Bader Lane, Kingston, ON K7L 3N6, Canada
a r t i c l e
i n f o
Article history: Received 16 November 2018 Received in revised form 7 March 2019 Accepted 16 March 2019 Available online 21 March 2019 Keywords: Adenosine phosphate Hydration Molecular dynamics simulation
a b s t r a c t The hydration behavior of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) has been investigated with molecular dynamics simulations. The spatial distribution of water molecules around different hydration sites of the adenosine phosphates and the average times that water molecules spend in the vicinity of the hydration sites of the phosphate, ribose, and adenine groups have been examined in order to characterize the hydration extent of different regions of the ATP, ADP, and AMP molecules. The water molecules strongly hydrate the negatively-charged phosphate groups of the adenosine phosphates and the interaction between the oxygen and nitrogen atoms of the ribose and adenine rings with water molecules lead to the full hydration of these groups by the water molecules as well. The adenosine phosphates ATP, ADP, and AMP were found to be fully hydrated by the water molecules regardless of the magnitude of their negative charges. Results of this work provide atomic-level information about the hydration of ATP, ADP, and AMP were and are expected to help better understand the behavior of these molecules in biological systems. © 2019 Published by Elsevier B.V.
1. Introduction Adenosine phosphates (AP) are key components of the energy flow in many biological systems. Adenosine-5′-triphosphate (ATP) is a cellular energy carrier which plays a critical role in metabolism [1–3]. One ATP molecule contains a ribose ring connected to one adenine and three phosphate groups [4]. The chemical energy stored in the phosphate bonds is released upon the hydrolysis of ATP which produces adenosine diphosphate (ADP) and one phosphate group [5]. The resulting ADP molecule can also produce a phosphate group and adenosine monophosphate (AMP) which is a building block of ribonucleic acid (RNA) [3]. The hydrolysis process can be reversed by enzymes such as ATP synthase which combine one ADP with a phosphate group to provide one ATP molecule [6,7]. The hydrolysis of ATP depends on the solvation energies of the hydrolysis reaction components and their interaction with the environment including enzyme active sites. Detailed investigation of the hydration behavior of adenosine phosphates provides molecular-level information that might be used to understand the mechanism of the ATP hydrolysis and also helps to understand the hydration behavior of large biomolecules containing adenosine phosphates [8–13]. The terminal phosphate groups of ATP, ADP and AMP are usually deprotonated in
⁎ Corresponding author. E-mail address: [email protected] (M. Sohrabi-Mahboub).
https://doi.org/10.1016/j.molliq.2019.03.085 0167-7322/© 2019 Published by Elsevier B.V.
the aqueous phase and their hydrated negatively charged ions are stable [14]. The hydration of adenosine phosphate series has been investigated with experimental and computational methods. High-resolution microwave dielectric relaxation spectroscopy has been applied to study the hydration properties of adenine nucleotides in aqueous solutions of ATP, ADP, and AMP [15]. It was found that the dielectric properties of the solutions have two Debye components characterized by two distinguished relaxation frequencies [15]. One component has a higher relaxation frequency than that of bulk water and corresponds to hypermobile water while the other has a much lower relaxation frequency compared to that of bulk water and relates to constrained water [15]. This investigation demonstrated the presence of three or four layers of hyper-mobile water around the phosphoryl groups of adenine nucleotides which shows the significant effect of such groups on water structure [15]. The hydration properties of AMP and ATP molecules have also been investigated by means of dielectric spectroscopy in aqueous solution as well as gravimetric studies in solid films [16]. Results of these investigations also confirm the presence of water molecules bound by the solute as well as a large amount of bulk water [16,17]. The balance between the bound and bulk water might affect the metabolic processes that involve adenosine phosphates. The intramolecular conformations of ATP and ADP in aqueous solution have been investigated with high-energy X-ray diffraction. Results revealed that the interaction between the adenine and phosphate groups within the ATP and ADP molecules depends on the experimental conditions such as
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the pH and concentration [18]. Liao et al. investigated the conformational equilibria of ATP in aqueous solutions using molecular dynamics (MD) simulations. The free energies obtained from the simulations showed that Mg2+ ions are attached to the oxygen atoms of the two terminal (end) phosphates or of all three phosphates of ATP [19]. The hydration free energy of deprotonated AMP and ADP in the gas phase has been measured experimentally for clusters containing up to seven water molecules [20]. The experimental results provided evidence for the presence of intramolecular hydrogen bonds and also indicated that the hydration free energies decrease in larger clusters [20]. Electrospray ionization mass spectrometry investigations on the stabilization of the excess charges in singly- and multiply-charged anions of ADP and ATP revealed that the adenine group stabilizes the negatively charged phosphate groups [21]. Theoretical findings also confirm the role of intra-molecular hydrogen bonds as well as solvent molecules in stabilizing the anions in the gas phase [21]. In this work, the hydration of adenosine phosphates is investigated with atomistic molecular dynamics simulation. In particular, the hydration characteristics of various hydration sites on the ribose, adenine and phosphate groups of AMP, ADP, and ATP and also the effect of hydration on the structural features of the anions have been investigated in detail. The theoretical procedure is presented in Section 2. Results are presented and discussed in Section 3 and conclusions are provided in Section 4. 2. Computational details The MD simulations were performed on the deprotonated AMP, ADP, and ATP molecules in 30 × 30 × 30 Å3 cubic boxes containing 800 water molecules. Sodium cations were used as counterions to compensate for the negative charges of AP which are −2, −3 and −4 for AMP, ADP, and ATP, respectively. The CHARMM27 all-atom force field [22,23] was used to describe the AP series and their interaction with Na+ ions and the transferable interaction potential with three points (TIP3P) model [24–26] was used to describe water. The isothermal-isobaric (NPT) ensemble with periodic boundary conditions and minimum-image convention in all three directions were used in all simulations. A cut-off distance of 12.0 Å was used for the van der Waals interactions and the forces were smoothly shifted to zero. The smooth particle mesh Ewald (SPME) [27] algorithm was applied to treat the long-range electrostatic interactions. The simulations were performed at 298 K and 1 atm with Langevin dynamics [28,29] and the Berendsen barostat [30] for keeping the temperature and pressure constant, respectively. The Langevin dynamics damping coefficient was set to of 5 ps−1, the Berendsen pressure relaxation time was set to 100.0 fs and the Berendsen pressure frequency was set to 10 fs. The equations of motion were integrated with the Velocity-Verlet algorithm [31] with a time step 1 fs. All systems were simulated for 2 ns, where the first 0.1 ns was used for equilibration. The MD simulations were performed with the NAMD program [32] and the results were analyzed and visualized using visual molecular dynamics (VMD) program [33]. The packmol program [34] was used to generate the initial simulation cells. The interaction energies (ΔEint) between the adenosine phosphate ions and water molecules were calculated with the self-consistentcharge density functional tight-binding method with third order corrections (DFTB3) [35,36]. The method has been validated and applied for a wide range of ion-water interactions previously [37–39]. The DFTB3 optimizations were performed with the conjugate gradient method with a maximum force tolerance of 1 × 10−5 au. The tolerance for the selfconsistent-charge iterations was set to 1 × 10−5 au. All DFTB3 calculations were performed with the 3ob set of parameters [40] using the DFTB+ code [41]. 3. Results and discussion The hydration behavior of the adenosine phosphate series was investigated by evaluating the spatial distribution of water molecules
around the phosphates, ribose and adenine groups of ATP4−, ADP3−, and AMP2− as well as Na+ ions. The translational mobility of the water molecules around AMP2−, ADP3−, and ATP4− ions was evaluated by calculating the average as well as the maximum time that water molecules of the first hydration shell spend around the ion hydration sites. Furthermore, the orientation of the water molecules around the AP hydration sites was investigated by evaluating the angle between the water dipoles and the vector connecting the hydration sites to the water oxygen atoms. 3.1. Spatial distribution of the water molecules The spatial distribution of the water molecules near different atoms of the AP molecules provides useful insight into the hydration characteristics of the phosphate, ribose and adenine groups. The radial distribution functions (RDF) provides a measure of the probability of finding molecules near a specific target. In this work, the RDF of the water oxygen (Ow) around the phosphorus, oxygen and nitrogen atoms of the adenine phosphate molecules are calculated in order to investigate the local interaction of the water molecules with the phosphate, ribose and adenine groups, respectively. The corresponding RDFs will be referred to as Px-Ow, Ox-Ow, and Nx-Ow, where x represents the atomic labels defined in Fig. 1. The RDFs obtained from the MD simulation trajectories are presented in Figs. 2–4. The RDFs obtained for Pα-Ow, Pβ-Ow, and Pγ-Ow in solutions containing AMP2−, ADP3−, ATP4−, and Na+ ions exhibits a wellpronounced peak around at 3–4 nm corresponding to the first hydration shell of the water molecules. Interestingly, the shape and the position of the RDF obtained for the terminal P groups are similar for all adenosine phosphate systems. In the case of ATP, the first Pβ-Ow and Pγ-Ow peaks are shifted towards higher distances and their height is declined compared to the Pα-Ow peak. This observation means that the middle phosphate groups of ATP have less interaction with the water molecules as they have been partially covered by the ribose or the terminal phosphate groups. The Pα-Ow, Pβ-Ow peaks obtained for ADP have similar heights but the Pβ-Ow peak is slightly shifted towards larger distances, again due to the smaller exposure of the middle phosphate group of ADP to the water molecules. The Pα-Ow RDFs obtained for all adenosine phosphate shows only one significant peak demonstrating the lack of a second hydration shell of the water molecules around the corresponding phosphate groups. The Pβ-Ow and Pγ-Ow RDFs of ADP and ATP have small second shoulders which are very likely due to the first hydration shell of water molecules around the neighboring phosphate groups. These observations clearly indicate the formation of one well-pronounced shell of water molecules around the phosphate groups of the AP without a significant restructuring of water beyond this first shell. The presence of this tight shell of water molecules around the negatively charged phosphate groups in consistent with the results of high-resolution microwave dielectric relaxation spectroscopy which provide experimental evidence for the presence of constrained water around the AP molecules [15]. The Ox-Ow RDFs, which measure the probability of finding water molecules around the oxygen atoms of the ribose rings of AP, are presented in Fig. 3. The RDFs obtained for the oxygen atoms of the OH groups have analogous features and both include one well-defined peak at 3 nm which corresponds to a shell of water molecules hydrogen bonded to the OH groups of the ribose ring. The O4-Ow RDFs also have a small peak around 3 nm due to the presence of water molecules interacting with O4 of the ribose ring although the height of these peaks are much smaller than those obtained for OH groups. Inspection of the simulation trajectories indicates that the OH groups of the ribose ring are hydrogen bond donors to the water molecules while the O4 atom can only accept hydrogen bonds from the water. The hydrogen atoms of the OH groups the ribose ring are more exposed and can easily interact with water molecules while the O4 atom of the ring buried
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Fig. 1. Structure and numbering scheme for adenosine phosphates in deprotonated form.
inside the molecule and can barely form direct hydrogen bonds with the water molecules. The Nx-Ow RDFs obtained for the AP are presented in Fig. 4. All RDFs increase to ~1.1 at distances around 3 nm and slightly fluctuates without showing any significant peak analogous to those observed for the phosphate and ribose OH groups. This observation points to the lack of any significant restructuring of the water molecules around the adenine groups of AMP2−, ADP3−, and ATP4−. However, it should be noted that the N6-Ow RDFs have a slightly more clear peak compared to the other nitrogen atoms which might be due to the formation of stronger
bonds between these atoms and the water molecules. Overall, the RDFs demonstrate that the adenine groups of the AP interact weakly with the water molecules. The binding energies of one water molecule interacting with the N6 atoms of the adenine group are presented in Table 1. The values are −7.0, −7.4, and −6.6 kcal mol−1 for AMP2−, ADP3−, and ATP4−, respectively, which are about two times smaller than the binding energies obtained for the water molecules bound to the oxygen atoms of the phosphate groups (−15.8, −15.6, and −13.6 kcal mol−1 for AMP2−, ADP3−, and ATP4−, respectively) due to the presence of negative charges on the oxygen groups (cf. Table 1).
Fig. 2. RDFs obtained for the phosphorus atoms of AMP2−, ADP3−, and ATP4− and the oxygen atom of water.
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Fig. 3. RDFs obtained for the oxygen atoms of the ribose rings of AMP2−, ADP3−, and ATP4− and the oxygen atom of water.
The smaller binding energies of the N6-water interactions are consistent with the less structured RDFs obtained from the MD simulations. It is also noted that the time that each water molecules spends in the vicinity of the N6 atoms, 2.2–2.3 ps, are also about two times smaller than the corresponding time for the phosphate groups which is 4.4 ps. 3.2. Translational mobility of the water molecules In this section, the average number of water molecules in the first hydration shell (FHS) around the hydration sites of the AMP2−, ADP3−, and ATP4− ions was calculated. Additionally, the average time (τavg) that water molecules spend in FHS, and also the maximum time (τmax) that they stay in FHS were evaluated. The results have been tabulated in Tables 2–4. The average number of water molecules around the terminal phosphate groups of AMP2−, ADP3−, and ATP4− ions are 11, 10, and 7.3, respectively. The average time that these water molecules spend around the terminal phosphate groups are 56.6, 57.1, and 48.2 ps, respectively, while the maximum times that the water molecules spend in the hydration shell are 334, 428, and 488 ps, respectively. According to these results, a smaller number of water molecules hydrate
the terminal oxygen atoms of ATP4− ion, compared to AMP2− and ADP3−, and the average life-time of the water molecules in the hydration shell is shorter than those observed for AMP2− and ADP3−. This observation is consistent with the trend observed for the interaction energy between water and the terminal phosphate groups of the AP which indicates that ΔEint for ATP4−–H2O is ~8 kcal mol−1 smaller than those obtained for AMP2− and ADP3−. The Navg and τavg values obtained for water molecules around the terminal phosphates of AMP2− and ADP3− have similar values which is also consistent with the ion– water interaction energies obtained for these systems. The Navg, τavg, and τmax values obtained for the water molecules in the first hydration shells of the middle phosphate groups of ADP3− and ATP4− are all smaller than their corresponding values obtained for the terminal phosphate group. This is due to the decreased exposure of the middle phosphate groups towards the solvent molecules which prevents the formation of large and tightly-bound hydration shells of water around these phosphate groups. It is noted that the water molecules forming the first hydration shells around the middle phosphate groups of ATP4− have the smallest Navg and τavg values.
Fig. 4. RDFs obtained for the nitrogen atoms of the adenine groups of AMP2−, ADP3−, and ATP4− and the oxygen atom of water.
M. Sohrabi-Mahboub et al. / Journal of Molecular Liquids 283 (2019) 359–365 Table 1 Binding energies of one water molecules around Pα, Pβ, Pγ, atoms, oxygen atoms of ribose ring atoms and N6,7 atoms of adenine group. ΔEint (kcal mol−1)
ATP-series
−15.8 −10.9 −15.6 −7.42 −5.51 −13.6 −7.0 −7.4 −6.6
AMP (Pα-water) ADP (Pβ-water) ADP (Pα-water) ATP (Pγ-water) ATP (Pβ-water) ATP (Pα-water) AMP (N6,7-water) ADP (N6,7-water) ATP (N6,7-water)
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Table 3 Coordination number (CN) of water around oxygen atoms of ribose ring and the average time (τavg) and the maximum time (τmax) that water molecules spend near O2, O3, O4 (the estimated error is ~1 ps and ~5 ps for τavg and τmax, respectively).
AMP (O2-Ow) AMP (O3-Ow) AMP (O4-Ow) ADP (O2-Ow) ADP (O3-Ow) ADP (O4-Ow) ATP (O2-Ow) ATP (O3-Ow) ATP (O4-Ow)
CN
τavg (ps)
τmax (ps)
7.7 7.4 6.6 6.8 6.8 5.3 5.7 6.4 4.9
23.7 22.6 33.4 22.5 22.7 26.7 23.3 23.4 22.6
136.0 124.0 278.0 124.0 134.0 310.0 530.0 214.0 234.0
Comparison of the Navg, τavg, and τmax values obtained for the water molecules around the ribose oxygen atoms reveals that the hydration shell around the O4 atoms of the ribose ring contains a smaller number of water molecules which have shorter τavg and τmax values compared to the hydration shells around the O2 and O3 atoms. This observation is consistent with the RDFs obtained for the water molecules around these hydration sites in all three adenosine phosphate ions. The ΔEint obtained for the O2–water interactions are 4.7, 4.4, and 4.3 kcal mol−1 which are much smaller than the values obtained for the interaction between water and the phosphate groups. It is also noted that the τavg values obtained for the hydration sites of the ribose ring are significantly smaller than those obtained for the phosphate groups reflecting the higher interaction between the water molecules and negativelycharged oxygen atoms of the phosphate groups. The τavg values are also smaller than those of phosphate groups in most cases. The average number of water molecules in the first hydration shells of adenine hydration sites is slightly smaller than those obtained for the ribose ring and the phosphate groups. The τavg and τmax values are generally smaller than those obtained for the ribose and phosphate groups except the values calculated for the N6 and N7 atoms. These two atoms have the most recognizable first hydration shell, according to the RDFs, compared to the other N atoms. The water molecules interacting with the N6 and N7 atoms of the adenine group in all ions, form a very stable structure with these to N atoms. In fact, one water molecule acts as both hydrogen bonds donor and acceptor with respect to the N6 and N7 atoms, respectively. The interaction energies of the water molecule with the N6-N7 site are −7.0, −7.4, and −6.6 kcal mol−1 for AMP2−, ADP3−, and ATP4−, respectively, which are comparable to the values obtained for the terminal phosphate group of ATP4−. Comparison of the average and the maximum time that the water molecules spend various hydration sites of AP is in agreement with the experimental results of high-resolution microwave dielectric relaxation spectroscopy and further confirms the presence of tightly bonded water molecules near the negatively charged phosphate groups.
AMP2− has two peaks which one of them is distributed between 0 and 90° with a maximum of around 45°. The second peak is much smaller and is distributed between 90°–180° with a maximum of around 125°. The first peak corresponds to the water molecules in which hydrogen atoms are oriented towards the phosphate oxygens and the second peaks are very likely due to the interaction of water oxygens with the Na+ atoms. The Pα–Ow dipole distributions in ADP3− and ATP4− also have a large peak between 0 and 90° while their Pβ– Ow and Pγ–Ow dipole distributions have more pronounced second peaks between 90 and 180°. The presence of these distinct peaks with maximum values of around 45° and 125° reveals that the water molecules around the phosphate groups have a rather rigid orientation. The dipole distributions of the water molecules around the O4 ribose hydration sites in all adenosine phosphate ions have a peak between 0 and 90° analogous to the Pα–Ow dipole distributions. The dipole distributions corresponding to the O2 and O3 atoms are almost identical and are broader compared to the O4–Ow dipole distributions. The broader peaks of the O2,3–Ow distributions can be related to the higher freedom of the water molecules around these atoms compared to the O4 hydration site. The N–Ow dipole distributions have very broad peaks between 0 and 180° again because of the higher freedom of the water molecules around these hydration sites. The broad peaks around the adenosine hydration sites are consistent with the broad RDFs obtained for these systems which are related to the presence of less structured water molecules around these hydration sites. The difference in the hydration extent of different regions of the AP anions, as reflected in the RDFs, residential times and orientational dynamics of the water molecules around various hydration sites of APs, is expected to affect the interaction of AP anions with other biological molecules. The less hydrated adenosine residues might better interact with hydrophobic regions of larger biomolecules and show higher affinity towards interfacial region
3.3. Orientational dynamics of the water molecules
Table 4 Coordination number (CN) of water around nitrogen atoms of adenine and the average time (τavg) and the maximum time (τmax) that water molecules spend near N1, N3, N6, N7, N9 (the estimated error is ~1 ps and ~5 ps for τavg and τmax, respectively).
The distribution of the angles between the vector that connects the water oxygens to the center of the hydrated sites and the water dipole vectors are plotted in Figs. 5–7. The Pα–Ow dipole distribution in Table 2 Coordination number (CN) of water around Pα, Pβ, Pγ, atoms and the average time (τavg) and the maximum time (τmax) that water molecules spend near Pα, Pβ, Pγ (the estimated error is ~1 ps and ~5 ps for τavg and τmax, respectively). CN AMP (Pα-Ow) ADP (Pβ-Ow) ADP (Pα-Ow) ATP (Pγ-Ow) ATP (Pβ-Ow) ATP (Pα-Ow)
11.0 10.0 7.9 7.3 6.7 6.9
τavg (ps)
τmax (ps)
56.6 57.1 43.9 48.2 35.9 35.0
334.0 428.0 328.0 488.0 378.0 278.0
AMP (N1-Ow) AMP (N3-Ow) AMP (N6-Ow) AMP (N7-Ow) AMP (N9-Ow) ADP (N1-Ow) ADP (N3-Ow) ADP (N6-Ow) ADP (N7-Ow) ADP (N9-Ow) ATP (N1-Ow) ATP (N3-Ow) ATP (N6-Ow) ATP (N7-Ow) ATP (N9-Ow)
CN
τavg (ps)
τmax (ps)
6.9 6.8 8.7 7.6 5.4 6.0 6.2 7.1 6.4 4.9 6.1 5.9 7.8 6.7 4.7
20.2 20.8 25.8 25.7 19.2 18.8 20.6 22.9 23.9 18.8 18.8 19.2 23.9 25.8 19.4
134 164 170 202 150 156 190 134 226 274 120 262 146 442 452
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Fig. 5. Distribution of the angle between the water dipoles and the vector connecting the hydration sites of AMP2− to the water oxygen atoms.
as observed for other classes of organic ions [42] and also anions of the Hofmeister series [43,44]. The presence of differently hydrated regions might also lead to the aggregation of AP anions in aqueous solutions. 4. Conclusions Molecular dynamics simulations have been performed to investigate the hydration behavior of AP including ATP, ADP, and AMP. The radial distribution functions of the water molecules in the vicinity of the phosphate groups have well-defined peaks as a result of the strong interaction between the water hydrogens and the negatively-charged oxygen atoms of the phosphate groups of the AP. The water radial distribution functions obtained for the ribose and adenine groups have much smaller peaks compared to those obtained for the phosphate groups. The average time that water molecules stay in the first hydration shell of the phosphate groups were found to be 1.5–2 times larger than those obtained for the ribose and adenine groups which is consistent with strong interactions of the water molecules with the phosphate
groups of AP. The orientation of the water molecules around different regions of the AP also confirm that water molecules are more tightly bound to the phosphate groups. According to these observations, it is concluded that the phosphate groups of AMP, ADP, and ATP are more tightly wrapped by distinct shells of water molecules while the ribose and adenine groups are loosely surrounded by the water molecules. However, despite the localization of the negative charges on the phosphate groups, the presence of multiple hydration sites on the ribose and adenine rings make the whole molecules to be fully hydrated. Furthermore, the strong interactions between the oxygen atoms of the phosphate groups and water molecules lead to the formation of more structured networks of water around the phosphate groups. Further investigations of the difference in the hydration extents of different regions of AP will provide more insight into the hydration behavior of these important molecules at interfaces. Nomenclature ATP adenosine-5′-triphosphate
Fig. 6. Distribution of the angle between the water dipoles and the vector connecting the hydration sites of ADP3− to the water oxygen atoms.
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Fig. 7. Distribution of the angle between the water dipoles and the vector connecting the hydration sites of ATP4− to the water oxygen atoms.
ADP AMP RNA AP FHS MD TIP3P
adenosine-5′-diphosphate adenosine-5′-monophosphate ribonucleic acid adenosine phosphates first hydration shell molecular dynamics transferable interaction potential with three points water model CHARMM Chemistry at HARvard Molecular Mechanics NPT isothermal-isobaric statistical mechanical ensemble PME particle mesh Ewald VMD visual molecular dynamics DFTB3 density functional tight-binding method with third order corrections RDF radial distribution functions Ow oxygen of water Hw hydrogen of water
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