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Double amino acid – A novel molecule enabling peptide interpenetrating structures
Chemical Physics Letters 599 (2014) 34–37
Contents lists available at ScienceDirect
Chemical Physics Letters journal homepage: www.elsevier.com/locate/cplett
Double amino acid – A novel molecule enabling peptide interpenetrating structures Sylwia Freza, Marzena Marchaj, Piotr Skurski ⇑ ´ sk, Wita Stwosza 63, 80-308 Gdan ´ sk, Poland Department of Chemistry, University of Gdan
a r t i c l e
i n f o
Article history: Received 23 February 2014 In final form 6 March 2014 Available online 14 March 2014
a b s t r a c t Peptide chains might be linked with one another using various external bifunctional molecules. We postulate an existence of a novel molecule termed ‘double amino acid’ containing four functional groups connected to one C atom ((NH2)2C(COOH)2). Using correlated ab initio approach (QCISD and MP2 methods) we provide its structure, simulated IR spectrum and verify its stability in gas and aqueous phases. The proposed double amino acid is predicted to enable the design of a novel family of interpenetrating peptides in which it is expected to serve as a built-in amino acid residue that might be shared by two independent peptide chains. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction
2. Methods
The importance of amino acids is undisputable. Assembled into various proteins, the amino acids (AA) comprise the second largest component of human cells and tissues. Their natural ability to group into chains (peptides) [1,2] and to form large and complicated structures (such as proteins) is constantly investigated, both experimentally and theoretically. The proteinogenic AAs attract obvious and understandable attention, however, the significance of natural but non-proteinogenic (i.e., not encoded in the genetic code) amino acids has also been confirmed [3]. Although various types of higher-order peptide and protein structures have already been investigated thoroughly, the possible existence of mutually interpenetrating peptides (formed by sharing amino acid residues) has not been considered thus far. In this Letter, we postulate the possible existence of an amino acid that may serve as a peptide linkage of new type due to its tetrafunctional structure. In particular, the system we propose, when assembled into a peptide chain, should enable the formation of peptide interpenetrating structures (rather than crosslinked peptides obtained with commonly used bifunctional reactants). The predicted structures of two representative species of such interpenetrating peptides (composed of a-helix Ala chains) are demonstrated and discussed.
The preliminary search for various isomeric (NH2)2C(COOH)2 (labeled DAA) structures was initially performed using the second-order Møller–Plesset perturbational method (MP2) and the aug-cc-pVDZ basis set [4] and then refined by employing the quadratic configuration interaction method including single and double substitutions (QCISD) [5–7] and the same aug-cc-pVDZ basis set (both in the gas phase and including solvent effects). The final equilibrium structures and harmonic vibrational frequencies were determined using the QCISD method with the aug-cc-pVDZ basis set. The reported Gibbs free energies (DG) for decarboxylation of both DAA (i.e., canonical DAA) and +DAA (i.e., half- and fully-zwitterionic DAA) were obtained at the QCISD/aug-cc-pVDZ level whereas those for the remaining larger systems (DAA(Ala)4 in its canonical and zwitterionic forms) were calculated using the B3LYP method [8,9] and the 6 31 + G⁄ basis set [10,11]. The equilibrium geometries of DAA(Ala)4 in its canonical, half-zwitterionic, and fully-zwitterionic structures, as well as the structure of the DAA(Ala)12 were determined at the B3LYP/6 31 + G⁄ level. The effects of surrounding water molecules were approximated by employing the polarized continuum solvation model (PCM) [12– 14] within a self-consistent reaction field treatment, as implemented in the GAUSSIAN09 program (the default options for PCM and the dielectric constant of 78.39 for water were used). All calculations were performed using the GAUSSIAN09 program package [15]. 3. Results and discussion
⇑ Corresponding author. E-mail address: [email protected] (P. Skurski). http://dx.doi.org/10.1016/j.cplett.2014.03.020 0009-2614/Ó 2014 Elsevier B.V. All rights reserved.
The novel molecule we propose is described by the (NH2)2C(COOH)2 formula and consists of two amino and two carboxyl
S. Freza et al. / Chemical Physics Letters 599 (2014) 34–37
groups connected to the same C atom. Formally, any organic compound with an amine and a carboxylic acid functional group is an amino acid. Albeit most proteinogenic a-amino acids possess hydrogen atom linked to the a-carbon, this is not always the case (known exceptions include amino isobutyric acid and dehydroalanine). Thus, the molecule whose possible existence and stability we postulate, given by the (NH2)2C(COOH)2 formula, might be termed an amino acid, despite the absence of hydrogen atom on the a-carbon. Moreover, we suggest to term it a ‘double amino acid’ (DAA) since the number of its functional groups is doubled with respect to a regular AA. We found several isomers of DAA that are locally geometrically stable (in aqueous and gas phases). As expected, canonical structures ((NH2)2C(COOH)2) dominate in the gas phase, whereas halfzwitterionic ((NH+3)(NH2)C(COOH)(COO ), labeled +DAA ) and fully-zwitterionic ((NH+3)2C(COO )2, labeled ++DAA ) forms are predicted to predominate in the presence of water solvent [16] (whose influence was approximated by employing the polarized continuum solvation model as implemented in GAUSSIAN09 package). The equilibrium structures of the most stable isomers in both gas and aqueous phases are presented in Figure 1 together with the corresponding simulated IR spectra (to enable their future experimental identification). The global minimum predicted for the gas phase corresponds to the canonical form of DAA (with two NH2 and two COOH groups intact) whereas the half-zwitterionic form (+DAA ) was found to be the most stable in aqueous solution. The geometrical structures and harmonic vibrational frequencies characterizing these species (obtained using the QCISD method
35
with the aug-cc-pVDZ basis set) indicate that the hydrogen bonds formed between the amino and carboxyl groups are crucial for their stability. Albeit the presented structures represent the global minima, other low-energy isomers/conformers were also predicted (i.e., three and five isomeric structures in gas and aqueous phase, respectively) to be competitive as their relative energies do not exceed those of the most stable structures by more than 5 kcal/mol. Most of those low-energy isomers, however, are in fact conformers that differ from one another only by mutual functional group orientations and thus the resulting H-bond network. Due to its rather untypical structure (two carboxyl groups bound to the same C atom), the stability of the DAA might be questioned. Since decarboxylation is the most intuitive and probable fragmentation process this system may be vulnerable to, we verified the stability of DAA with respect to CO2 loss. As expected, we found canonical DAA to be susceptible to decarboxylation in the gas phase (the Gibbs free energy (DG) for this reaction is 16.4 kcal/mol) which is typical also for various common amino acids (DG values for the analogous reactions involving isolated glycine and alanine read 16.7 and 15.6 kcal/mol, respectively, as we determined at the same theory level). In the presence of polar solvent (water), however, typical amino acids exist as zwitterions and are stable with respect to decarboxylation. Indeed, the positive DG values of ca. 50–54 kcal/mol are predicted for zwitterionic glycine and alanine when the CO2 loss is considered at such conditions. Analogous observations might also be made for simple peptides, e.g., we found the Ala-Ala-Ala tripeptide to be unstable in gas phase (DG = 8 kcal/mol) but stable in water (DG = 62 kcal/
Figure 1. The equilibrium structures of the most stable isomers of DAA in gas (top) and aqueous (bottom) phase. The corresponding simulated IR spectra are based on the calculated harmonic vibrational frequencies (the lorentzian peaks with fwhm of 54 cm 1 were assumed). Selected vibrations are indicated with: b-bending, m-stretching, s-symmetrical, as-asymmetrical, sc-scissoring, u-umbrella. The presented geometrical structures and vibrational frequencies were determined at the QCISD/aug-cc-pVDZ level.
36
S. Freza et al. / Chemical Physics Letters 599 (2014) 34–37
mol) with respect to decarboxylation reaction. The DAA system is predicted to exist in water as a half-zwitterion (shown in Figure 1, bottom) and we found this structure to be stable with respect to decarboxylation, which is confirmed by the positive value (29 kcal/mol) of the Gibbs free energy determined for the process leading to the CO2 loss. Hence, we conclude that the proposed DAA exhibits very similar behavior to common natural amino acids when the stability with respect to decarboxylation is concerned: (i) similarly to natural amino acids, the canonical DAA dominates in the gas phase and is susceptible to CO2 loss; and, (ii) also analogously to common natural amino acids, the ionic +DAA (i.e., its half-zwitterionic form) dominates in aqueous phase and is not susceptible to decarboxylation. It is important to discuss the possible role the proposed double amino acid might play when assembled into larger structures (such as peptides and proteins). The most important property of DAA is the accessibility of its four functional groups which may lead to the formation of four peptide bonds. We demonstrate this by presenting a simple molecular example in which the DAA system utilizes its two amino groups and two carboxyl groups to bind four Ala amino acids through peptide bonds (see Figure 2). The lowest energy structures (both in gas phase and water) of
Figure 2. The schematic representation of the DAA(Ala)4 system (top) with four Ala amino acids (represented by arrows) linked to the central DAA via peptide bonds. The equilibrium structures of the most stable isomers in both phases are also presented: the canonical DAA(Ala)4 for the gas phase (middle) and half-zwitterionic + [DAA(Ala)4] for the aqueous phase (bottom).
DAA(Ala)4 contain the double amino acid in the center and four Ala molecules (each of which linked to the different functional group of DAA). Analogously to the findings we described for the isolated DAA system, the canonical and half-zwitterionic form of DAA(Ala)4 is expected to dominate in the gas and aqueous phase, respectively. Clearly, to distinguish between the canonical and zwitterionic forms of the DAA(Ala)4 system, one has to analyze the functional groups of Ala that are not involved in bond formation, as all four functional groups of the central DAA unit are engaged in peptide bonds. The equilibrium structure of the canonical minimum energy DAA(Ala)4 seems intuitive with its two COOH groups forming internal H-bonds, while the proximity of the positively charged NH3 and negatively charged COO groups in the half-ionized DAA(Ala)4 attracts attention, see Figure 2. Similarly to the isolated DAA molecule and natural amino acids, the canonical DAA(Ala)4 in the gas phase is unstable with respect to CO2 loss (DG = 10 kcal/mol), whereas the half-ionized DAA(Ala)4 (i.e., +DAA(Ala)4 ) is not susceptible to decarboxylation when the polar solvent (water) is present (DG for this reaction was estimated
Figure 3. The equilibrium structure of the DAA(Ala)12 molecule in the gas phase shown as: (i) alpha-helices (represented by ribbons) sharing the central DAA unit (top view), and (ii) all-atom representation with the DAA residue in the middle (bottom view).
S. Freza et al. / Chemical Physics Letters 599 (2014) 34–37
to read 61 kcal/mol). Hence, we conclude that the DAA molecule may indeed be assembled into larger peptide-like structures in which it might utilize its four functional groups. As a consequence, the interpenetrating peptide structures can be formed (with the DAA unit shared by two peptide chains and serving as a ‘peptidecrossroad’). The most important difference between such a demonstrated structure and the well-known cross-linked peptides [17,18] is the fact that the latter are simply the independent peptide chains linked through the linker units (e.g., carbodiimides, maleimides, pyridyl disulfides, glutaraldehyde, imidoesters) [19,20] which are external bifunctional reagents introduced to form covalent bonds with various functional groups of peptides and proteins, whereas the former corresponds to the peptide chains that share an amino acid and hence may interpenetrate each other. As a consequence, two peptide chains may be ‘combined’ with each other (rather than linked through a bifunctional reagent) which opens the door to designing a whole variety of novel peptide structures utilizing the double amino acid molecule presented in this Letter. The example of one of the simplest structures that might be designed using DAA is demonstrated in Figure 3. Namely, the presented equilibrium structure of the DAA(Ala)12 system may be treated as composed of two peptide chains (each of which is represented by an a-helix containing 7 amino acid (Ala) residues) sharing the DAA. Further investigations on the structures and properties of such designed interpenetrating peptides are in progress in our group. Finally, we would like to emphasize our hope that the novel double amino acid molecule whose existence and stability we postulate in this Letter, will allow to design a number of new peptide and protein structures containing chains interpenetrating one another in various ways. We believe that the simplest tetrafunctional
37
amino acid system is the key element that will enable the exploration of a new family of such peptide-based compounds. Acknowledgment This work was supported by the Polish Ministry of Science and Higher Education Grant No. DS/530-8371-D191-14 and partially by the Polish National Science Center (NCN) Grant No. N N519 641640. References [1] N. Sewald, H.-D. Jakubke, Peptides: Chemistry and Biology, WILEY-VCH Verlag GmbH & Co. KGaA, 2002. p. 7. [2] T.E. Creighton, Protein Structure and Molecular Properties, Freeman, New York, 1993. [3] C. Vermeer, Biochem. J. 266 (1990) 625. [4] R.A. Kendall, T.H. Dunning Jr., R.J. Harrison, J. Chem. Phys. 96 (1992) 6796. [5] J.A. Pople, M. Head-Gordon, K. Raghavachari, J. Chem. Phys. 87 (1987) 5968. [6] J. Gauss, D. Cremer, Chem. Phys. Lett. 150 (1988) 280. [7] E.A. Salter, G.W. Trucks, R.J. Bartlett, J. Chem. Phys. 90 (1989) 1752. [8] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785. [9] A.D. Becke, Phys. Rev. A 38 (1988) 3098. [10] A.D. McLean, G.S. Chandler, J. Chem. Phys. 72 (1980) 5639. [11] R. Krishnan, J.S. Binkley, R. Seeger, J.A. Pople, J. Chem. Phys. 72 (1980) 650. [12] S. Miertuš, E. Scrocco, J. Tomasi, Chem. Phys. 55 (1992) 117. [13] S. Miertuš, J. Tomasi, Chem. Phys. 65 (1982) 239. [14] M. Cossi, V. Barone, R. Cammi, J. Tomasi, Chem. Phys. Lett. 255 (1996) 327. [15] M.J. Frisch et al., GAUSSIAN09 (Rev.A.02), Gaussian, Inc., Wallingford, CT, 2009. [16] C.R. Cantor, P.R. Schimmel, Biophysical Chemistry, Part I, W. H. Freeman and Company, New York, 1980. p. 41. [17] G.A. Means, R.E. Feeney, Chemical Modification of Proteins, Holden Day, Inc., San Francisco, Cambridge, London, Amsterdam, 1971. p. 5. [18] R.H. Nagaraj, I.N. Shipanova, F.M. Faust, J. Biol. Chem. 271 (1996) 19338. [19] R.A. Sperling, W.J. Parak, Phil. Trans. R. Soc. A 368 (2010) 1333. [20] E. Valeur, M. Bradley, Chem. Soc. Rev. 38 (2009) 606.
Contents lists available at ScienceDirect
Chemical Physics Letters journal homepage: www.elsevier.com/locate/cplett
Double amino acid – A novel molecule enabling peptide interpenetrating structures Sylwia Freza, Marzena Marchaj, Piotr Skurski ⇑ ´ sk, Wita Stwosza 63, 80-308 Gdan ´ sk, Poland Department of Chemistry, University of Gdan
a r t i c l e
i n f o
Article history: Received 23 February 2014 In final form 6 March 2014 Available online 14 March 2014
a b s t r a c t Peptide chains might be linked with one another using various external bifunctional molecules. We postulate an existence of a novel molecule termed ‘double amino acid’ containing four functional groups connected to one C atom ((NH2)2C(COOH)2). Using correlated ab initio approach (QCISD and MP2 methods) we provide its structure, simulated IR spectrum and verify its stability in gas and aqueous phases. The proposed double amino acid is predicted to enable the design of a novel family of interpenetrating peptides in which it is expected to serve as a built-in amino acid residue that might be shared by two independent peptide chains. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction
2. Methods
The importance of amino acids is undisputable. Assembled into various proteins, the amino acids (AA) comprise the second largest component of human cells and tissues. Their natural ability to group into chains (peptides) [1,2] and to form large and complicated structures (such as proteins) is constantly investigated, both experimentally and theoretically. The proteinogenic AAs attract obvious and understandable attention, however, the significance of natural but non-proteinogenic (i.e., not encoded in the genetic code) amino acids has also been confirmed [3]. Although various types of higher-order peptide and protein structures have already been investigated thoroughly, the possible existence of mutually interpenetrating peptides (formed by sharing amino acid residues) has not been considered thus far. In this Letter, we postulate the possible existence of an amino acid that may serve as a peptide linkage of new type due to its tetrafunctional structure. In particular, the system we propose, when assembled into a peptide chain, should enable the formation of peptide interpenetrating structures (rather than crosslinked peptides obtained with commonly used bifunctional reactants). The predicted structures of two representative species of such interpenetrating peptides (composed of a-helix Ala chains) are demonstrated and discussed.
The preliminary search for various isomeric (NH2)2C(COOH)2 (labeled DAA) structures was initially performed using the second-order Møller–Plesset perturbational method (MP2) and the aug-cc-pVDZ basis set [4] and then refined by employing the quadratic configuration interaction method including single and double substitutions (QCISD) [5–7] and the same aug-cc-pVDZ basis set (both in the gas phase and including solvent effects). The final equilibrium structures and harmonic vibrational frequencies were determined using the QCISD method with the aug-cc-pVDZ basis set. The reported Gibbs free energies (DG) for decarboxylation of both DAA (i.e., canonical DAA) and +DAA (i.e., half- and fully-zwitterionic DAA) were obtained at the QCISD/aug-cc-pVDZ level whereas those for the remaining larger systems (DAA(Ala)4 in its canonical and zwitterionic forms) were calculated using the B3LYP method [8,9] and the 6 31 + G⁄ basis set [10,11]. The equilibrium geometries of DAA(Ala)4 in its canonical, half-zwitterionic, and fully-zwitterionic structures, as well as the structure of the DAA(Ala)12 were determined at the B3LYP/6 31 + G⁄ level. The effects of surrounding water molecules were approximated by employing the polarized continuum solvation model (PCM) [12– 14] within a self-consistent reaction field treatment, as implemented in the GAUSSIAN09 program (the default options for PCM and the dielectric constant of 78.39 for water were used). All calculations were performed using the GAUSSIAN09 program package [15]. 3. Results and discussion
⇑ Corresponding author. E-mail address: [email protected] (P. Skurski). http://dx.doi.org/10.1016/j.cplett.2014.03.020 0009-2614/Ó 2014 Elsevier B.V. All rights reserved.
The novel molecule we propose is described by the (NH2)2C(COOH)2 formula and consists of two amino and two carboxyl
S. Freza et al. / Chemical Physics Letters 599 (2014) 34–37
groups connected to the same C atom. Formally, any organic compound with an amine and a carboxylic acid functional group is an amino acid. Albeit most proteinogenic a-amino acids possess hydrogen atom linked to the a-carbon, this is not always the case (known exceptions include amino isobutyric acid and dehydroalanine). Thus, the molecule whose possible existence and stability we postulate, given by the (NH2)2C(COOH)2 formula, might be termed an amino acid, despite the absence of hydrogen atom on the a-carbon. Moreover, we suggest to term it a ‘double amino acid’ (DAA) since the number of its functional groups is doubled with respect to a regular AA. We found several isomers of DAA that are locally geometrically stable (in aqueous and gas phases). As expected, canonical structures ((NH2)2C(COOH)2) dominate in the gas phase, whereas halfzwitterionic ((NH+3)(NH2)C(COOH)(COO ), labeled +DAA ) and fully-zwitterionic ((NH+3)2C(COO )2, labeled ++DAA ) forms are predicted to predominate in the presence of water solvent [16] (whose influence was approximated by employing the polarized continuum solvation model as implemented in GAUSSIAN09 package). The equilibrium structures of the most stable isomers in both gas and aqueous phases are presented in Figure 1 together with the corresponding simulated IR spectra (to enable their future experimental identification). The global minimum predicted for the gas phase corresponds to the canonical form of DAA (with two NH2 and two COOH groups intact) whereas the half-zwitterionic form (+DAA ) was found to be the most stable in aqueous solution. The geometrical structures and harmonic vibrational frequencies characterizing these species (obtained using the QCISD method
35
with the aug-cc-pVDZ basis set) indicate that the hydrogen bonds formed between the amino and carboxyl groups are crucial for their stability. Albeit the presented structures represent the global minima, other low-energy isomers/conformers were also predicted (i.e., three and five isomeric structures in gas and aqueous phase, respectively) to be competitive as their relative energies do not exceed those of the most stable structures by more than 5 kcal/mol. Most of those low-energy isomers, however, are in fact conformers that differ from one another only by mutual functional group orientations and thus the resulting H-bond network. Due to its rather untypical structure (two carboxyl groups bound to the same C atom), the stability of the DAA might be questioned. Since decarboxylation is the most intuitive and probable fragmentation process this system may be vulnerable to, we verified the stability of DAA with respect to CO2 loss. As expected, we found canonical DAA to be susceptible to decarboxylation in the gas phase (the Gibbs free energy (DG) for this reaction is 16.4 kcal/mol) which is typical also for various common amino acids (DG values for the analogous reactions involving isolated glycine and alanine read 16.7 and 15.6 kcal/mol, respectively, as we determined at the same theory level). In the presence of polar solvent (water), however, typical amino acids exist as zwitterions and are stable with respect to decarboxylation. Indeed, the positive DG values of ca. 50–54 kcal/mol are predicted for zwitterionic glycine and alanine when the CO2 loss is considered at such conditions. Analogous observations might also be made for simple peptides, e.g., we found the Ala-Ala-Ala tripeptide to be unstable in gas phase (DG = 8 kcal/mol) but stable in water (DG = 62 kcal/
Figure 1. The equilibrium structures of the most stable isomers of DAA in gas (top) and aqueous (bottom) phase. The corresponding simulated IR spectra are based on the calculated harmonic vibrational frequencies (the lorentzian peaks with fwhm of 54 cm 1 were assumed). Selected vibrations are indicated with: b-bending, m-stretching, s-symmetrical, as-asymmetrical, sc-scissoring, u-umbrella. The presented geometrical structures and vibrational frequencies were determined at the QCISD/aug-cc-pVDZ level.
36
S. Freza et al. / Chemical Physics Letters 599 (2014) 34–37
mol) with respect to decarboxylation reaction. The DAA system is predicted to exist in water as a half-zwitterion (shown in Figure 1, bottom) and we found this structure to be stable with respect to decarboxylation, which is confirmed by the positive value (29 kcal/mol) of the Gibbs free energy determined for the process leading to the CO2 loss. Hence, we conclude that the proposed DAA exhibits very similar behavior to common natural amino acids when the stability with respect to decarboxylation is concerned: (i) similarly to natural amino acids, the canonical DAA dominates in the gas phase and is susceptible to CO2 loss; and, (ii) also analogously to common natural amino acids, the ionic +DAA (i.e., its half-zwitterionic form) dominates in aqueous phase and is not susceptible to decarboxylation. It is important to discuss the possible role the proposed double amino acid might play when assembled into larger structures (such as peptides and proteins). The most important property of DAA is the accessibility of its four functional groups which may lead to the formation of four peptide bonds. We demonstrate this by presenting a simple molecular example in which the DAA system utilizes its two amino groups and two carboxyl groups to bind four Ala amino acids through peptide bonds (see Figure 2). The lowest energy structures (both in gas phase and water) of
Figure 2. The schematic representation of the DAA(Ala)4 system (top) with four Ala amino acids (represented by arrows) linked to the central DAA via peptide bonds. The equilibrium structures of the most stable isomers in both phases are also presented: the canonical DAA(Ala)4 for the gas phase (middle) and half-zwitterionic + [DAA(Ala)4] for the aqueous phase (bottom).
DAA(Ala)4 contain the double amino acid in the center and four Ala molecules (each of which linked to the different functional group of DAA). Analogously to the findings we described for the isolated DAA system, the canonical and half-zwitterionic form of DAA(Ala)4 is expected to dominate in the gas and aqueous phase, respectively. Clearly, to distinguish between the canonical and zwitterionic forms of the DAA(Ala)4 system, one has to analyze the functional groups of Ala that are not involved in bond formation, as all four functional groups of the central DAA unit are engaged in peptide bonds. The equilibrium structure of the canonical minimum energy DAA(Ala)4 seems intuitive with its two COOH groups forming internal H-bonds, while the proximity of the positively charged NH3 and negatively charged COO groups in the half-ionized DAA(Ala)4 attracts attention, see Figure 2. Similarly to the isolated DAA molecule and natural amino acids, the canonical DAA(Ala)4 in the gas phase is unstable with respect to CO2 loss (DG = 10 kcal/mol), whereas the half-ionized DAA(Ala)4 (i.e., +DAA(Ala)4 ) is not susceptible to decarboxylation when the polar solvent (water) is present (DG for this reaction was estimated
Figure 3. The equilibrium structure of the DAA(Ala)12 molecule in the gas phase shown as: (i) alpha-helices (represented by ribbons) sharing the central DAA unit (top view), and (ii) all-atom representation with the DAA residue in the middle (bottom view).
S. Freza et al. / Chemical Physics Letters 599 (2014) 34–37
to read 61 kcal/mol). Hence, we conclude that the DAA molecule may indeed be assembled into larger peptide-like structures in which it might utilize its four functional groups. As a consequence, the interpenetrating peptide structures can be formed (with the DAA unit shared by two peptide chains and serving as a ‘peptidecrossroad’). The most important difference between such a demonstrated structure and the well-known cross-linked peptides [17,18] is the fact that the latter are simply the independent peptide chains linked through the linker units (e.g., carbodiimides, maleimides, pyridyl disulfides, glutaraldehyde, imidoesters) [19,20] which are external bifunctional reagents introduced to form covalent bonds with various functional groups of peptides and proteins, whereas the former corresponds to the peptide chains that share an amino acid and hence may interpenetrate each other. As a consequence, two peptide chains may be ‘combined’ with each other (rather than linked through a bifunctional reagent) which opens the door to designing a whole variety of novel peptide structures utilizing the double amino acid molecule presented in this Letter. The example of one of the simplest structures that might be designed using DAA is demonstrated in Figure 3. Namely, the presented equilibrium structure of the DAA(Ala)12 system may be treated as composed of two peptide chains (each of which is represented by an a-helix containing 7 amino acid (Ala) residues) sharing the DAA. Further investigations on the structures and properties of such designed interpenetrating peptides are in progress in our group. Finally, we would like to emphasize our hope that the novel double amino acid molecule whose existence and stability we postulate in this Letter, will allow to design a number of new peptide and protein structures containing chains interpenetrating one another in various ways. We believe that the simplest tetrafunctional
37
amino acid system is the key element that will enable the exploration of a new family of such peptide-based compounds. Acknowledgment This work was supported by the Polish Ministry of Science and Higher Education Grant No. DS/530-8371-D191-14 and partially by the Polish National Science Center (NCN) Grant No. N N519 641640. References [1] N. Sewald, H.-D. Jakubke, Peptides: Chemistry and Biology, WILEY-VCH Verlag GmbH & Co. KGaA, 2002. p. 7. [2] T.E. Creighton, Protein Structure and Molecular Properties, Freeman, New York, 1993. [3] C. Vermeer, Biochem. J. 266 (1990) 625. [4] R.A. Kendall, T.H. Dunning Jr., R.J. Harrison, J. Chem. Phys. 96 (1992) 6796. [5] J.A. Pople, M. Head-Gordon, K. Raghavachari, J. Chem. Phys. 87 (1987) 5968. [6] J. Gauss, D. Cremer, Chem. Phys. Lett. 150 (1988) 280. [7] E.A. Salter, G.W. Trucks, R.J. Bartlett, J. Chem. Phys. 90 (1989) 1752. [8] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785. [9] A.D. Becke, Phys. Rev. A 38 (1988) 3098. [10] A.D. McLean, G.S. Chandler, J. Chem. Phys. 72 (1980) 5639. [11] R. Krishnan, J.S. Binkley, R. Seeger, J.A. Pople, J. Chem. Phys. 72 (1980) 650. [12] S. Miertuš, E. Scrocco, J. Tomasi, Chem. Phys. 55 (1992) 117. [13] S. Miertuš, J. Tomasi, Chem. Phys. 65 (1982) 239. [14] M. Cossi, V. Barone, R. Cammi, J. Tomasi, Chem. Phys. Lett. 255 (1996) 327. [15] M.J. Frisch et al., GAUSSIAN09 (Rev.A.02), Gaussian, Inc., Wallingford, CT, 2009. [16] C.R. Cantor, P.R. Schimmel, Biophysical Chemistry, Part I, W. H. Freeman and Company, New York, 1980. p. 41. [17] G.A. Means, R.E. Feeney, Chemical Modification of Proteins, Holden Day, Inc., San Francisco, Cambridge, London, Amsterdam, 1971. p. 5. [18] R.H. Nagaraj, I.N. Shipanova, F.M. Faust, J. Biol. Chem. 271 (1996) 19338. [19] R.A. Sperling, W.J. Parak, Phil. Trans. R. Soc. A 368 (2010) 1333. [20] E. Valeur, M. Bradley, Chem. Soc. Rev. 38 (2009) 606.