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Role of protein motions in function
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Physics of Life Reviews 10 (2013) 35–36 www.elsevier.com/locate/plrev
Comment
Role of protein motions in function Comment on “Comparing proteins by their internal dynamics: Exploring structure–function relationships beyond static structural alignments” by Cristian Micheletti Pratul K. Agarwal a,b,∗ a Annavitas Biosciences, 2519 Caspian Drive, Knoxville, TN, United States b Computational Biology Institute, and Computer Science and Mathematics Division, Oak Ridge National Laboratory,
Oak Ridge, TN, United States Received 17 October 2012; accepted 19 October 2012 Available online 26 October 2012 Communicated by E. Di Mauro and E. Shakhnovich
Like all objects made up of atoms, proteins also undergo internal motions. The nature and extent of internal motions depend on a protein’s structure and are driven by temperature, surrounding environment, and other factors. For typical proteins, the internal motions range over 12 orders of magnitude in time-scale (from femto-second to milli-seconds or even longer). Even though experimental techniques have long provided information about these motions, the success of using structural information to obtain mechanistic insights has overshadowed investigations of internal motions. A variety of investigators continue to report that these motions may not be just random thermodynamical fluctuations, but some of the motions may also play a role in the designated functions of the proteins [1]. Obtaining detailed information about protein motions and the role they play in protein function has been difficult, particularly because of the wide range of time-scales involved and the narrow resolution windows of individual instruments [2]. Therefore, the relationship between protein motions and protein function remains a much debated topic [1–3]. Computational techniques continue to provide new information about protein motions and the role they play in function. As described by C. Micheletti in his review article, a number of techniques have been developed and used to obtain information, ranging from low- to high-quality, about the internal motions of proteins [4]. The simplest models focus on overall protein shape (represented only by backbone atoms) and use harmonic approximations to obtain information about the intrinsic motions or modes. More detailed computational simulations (using molecular dynamics) allow investigation of motions from the atomistic to the full protein level. Although the phenomenon has been discussed for some time, only recently have investigations also focused on the anharmonicity associated with the global conformational fluctuations at long time-scales and their relevance for function [5]. If it is important for function, then it must be conserved is an axiom long acknowledged in the protein structure community. The same reasoning could also be used to probe the relevance of protein motions to the function. As DOI of original article: http://dx.doi.org/10.1016/j.plrev.2012.10.009. * Correspondence to: Computational Biology Institute, and Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak
Ridge, TN, United States. E-mail address: [email protected]. 1571-0645/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.plrev.2012.10.008
36
P.K. Agarwal / Physics of Life Reviews 10 (2013) 35–36
discussed in Micheletti’s article, a comparison of motions, using dynamics-based alignment and other methods, for a number of different enzyme families and super-families has provided new insights [4]. In many cases, similar protein folds show similar dynamics; this fact has been used as an argument that it is not surprising and also does not indicate anything about the role of motions in function. However, this question could be asked another way. Does the conservation or preservation of functionally relevant dynamics for protein function (such as enzyme catalysis) place another design limitation on the protein shape or fold [6]? Even under severe metabolic stress, large protein folds with distal regions from functional sites are preserved, and proteins with low sequence similarity can share the same overall shape. This could be an indication of the importance of motions of distal regions and the overall protein fold in function, an aspect that needs to be explored further. The debate regarding the role of protein dynamics has been intense. Part of the confusion concerns the definition of what dynamics is: Is it fast or slow time-scales? Or is it equilibrium or non-equilibrium? Is the role of dynamics related to attaining the right conformations for function, or is it much more direct, such as guiding the function of a protein like an enzyme along the reaction coordinate? This could possibly be addressed by joint experimental– computational investigations. Nonetheless, even with the available information, it is now clear that the paradigm protein structure encodes function may need to be extended to protein structure encodes dynamics, and together, structure–dynamics encode function [6]. This may help us in gaining a better understanding of proteins and in solving challenging problems such as designing more efficient enzymes and better medicines through allosteric modulation. As recently demonstrated, understanding of reaction-coupled protein motions could be used to develop strategies for conformational modulation to design hyper-catalytic enzymes, with an 800 to 5200% increase in catalytic activity [7]. References [1] Hammes-Schiffer S, Benkovic SJ. Relating protein motion to catalysis. Annu Rev Biochem 2006;75:519–41. [2] Henzler-Wildman KA, Lei M, Thai V, Kerns SJ, Karplus M, Kern D. A hierarchy of timescales in protein dynamics is linked to enzyme catalysis. Nature 2007;450(7171):913–6. [3] Kamerlin SCL, Warshel A. At the dawn of the 21st century: is dynamics the missing link for understanding enzyme catalysis? Proteins 2009;78(6):1339–75. [4] Micheletti C. Comparing proteins by their internal dynamics: exploring structure–function relationships beyond static structural alignments. Phys Life Rev 2013;10:1–26 [in this issue]. [5] Ramanathan A, Savol A, Langmead CJ, Agarwal PK, Chennubhotla CS. Discovering conformational sub-states relevant to protein function. PLoS ONE 2011;6(1):e15827. [6] Ramanathan A, Agarwal PK. Evolutionarily conserved linkage between enzyme fold, flexibility, and catalysis. PLoS Biol 2011;9(11):e1001193. [7] Agarwal PK, Schultz C, Kalivreteno A, Ghosh B, Sheldon B. Engineering a hyper-catalytic enzyme by photo-activated conformation modulation. J Phys Chem Lett 2012;3:1142–6.
Physics of Life Reviews 10 (2013) 35–36 www.elsevier.com/locate/plrev
Comment
Role of protein motions in function Comment on “Comparing proteins by their internal dynamics: Exploring structure–function relationships beyond static structural alignments” by Cristian Micheletti Pratul K. Agarwal a,b,∗ a Annavitas Biosciences, 2519 Caspian Drive, Knoxville, TN, United States b Computational Biology Institute, and Computer Science and Mathematics Division, Oak Ridge National Laboratory,
Oak Ridge, TN, United States Received 17 October 2012; accepted 19 October 2012 Available online 26 October 2012 Communicated by E. Di Mauro and E. Shakhnovich
Like all objects made up of atoms, proteins also undergo internal motions. The nature and extent of internal motions depend on a protein’s structure and are driven by temperature, surrounding environment, and other factors. For typical proteins, the internal motions range over 12 orders of magnitude in time-scale (from femto-second to milli-seconds or even longer). Even though experimental techniques have long provided information about these motions, the success of using structural information to obtain mechanistic insights has overshadowed investigations of internal motions. A variety of investigators continue to report that these motions may not be just random thermodynamical fluctuations, but some of the motions may also play a role in the designated functions of the proteins [1]. Obtaining detailed information about protein motions and the role they play in protein function has been difficult, particularly because of the wide range of time-scales involved and the narrow resolution windows of individual instruments [2]. Therefore, the relationship between protein motions and protein function remains a much debated topic [1–3]. Computational techniques continue to provide new information about protein motions and the role they play in function. As described by C. Micheletti in his review article, a number of techniques have been developed and used to obtain information, ranging from low- to high-quality, about the internal motions of proteins [4]. The simplest models focus on overall protein shape (represented only by backbone atoms) and use harmonic approximations to obtain information about the intrinsic motions or modes. More detailed computational simulations (using molecular dynamics) allow investigation of motions from the atomistic to the full protein level. Although the phenomenon has been discussed for some time, only recently have investigations also focused on the anharmonicity associated with the global conformational fluctuations at long time-scales and their relevance for function [5]. If it is important for function, then it must be conserved is an axiom long acknowledged in the protein structure community. The same reasoning could also be used to probe the relevance of protein motions to the function. As DOI of original article: http://dx.doi.org/10.1016/j.plrev.2012.10.009. * Correspondence to: Computational Biology Institute, and Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak
Ridge, TN, United States. E-mail address: [email protected]. 1571-0645/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.plrev.2012.10.008
36
P.K. Agarwal / Physics of Life Reviews 10 (2013) 35–36
discussed in Micheletti’s article, a comparison of motions, using dynamics-based alignment and other methods, for a number of different enzyme families and super-families has provided new insights [4]. In many cases, similar protein folds show similar dynamics; this fact has been used as an argument that it is not surprising and also does not indicate anything about the role of motions in function. However, this question could be asked another way. Does the conservation or preservation of functionally relevant dynamics for protein function (such as enzyme catalysis) place another design limitation on the protein shape or fold [6]? Even under severe metabolic stress, large protein folds with distal regions from functional sites are preserved, and proteins with low sequence similarity can share the same overall shape. This could be an indication of the importance of motions of distal regions and the overall protein fold in function, an aspect that needs to be explored further. The debate regarding the role of protein dynamics has been intense. Part of the confusion concerns the definition of what dynamics is: Is it fast or slow time-scales? Or is it equilibrium or non-equilibrium? Is the role of dynamics related to attaining the right conformations for function, or is it much more direct, such as guiding the function of a protein like an enzyme along the reaction coordinate? This could possibly be addressed by joint experimental– computational investigations. Nonetheless, even with the available information, it is now clear that the paradigm protein structure encodes function may need to be extended to protein structure encodes dynamics, and together, structure–dynamics encode function [6]. This may help us in gaining a better understanding of proteins and in solving challenging problems such as designing more efficient enzymes and better medicines through allosteric modulation. As recently demonstrated, understanding of reaction-coupled protein motions could be used to develop strategies for conformational modulation to design hyper-catalytic enzymes, with an 800 to 5200% increase in catalytic activity [7]. References [1] Hammes-Schiffer S, Benkovic SJ. Relating protein motion to catalysis. Annu Rev Biochem 2006;75:519–41. [2] Henzler-Wildman KA, Lei M, Thai V, Kerns SJ, Karplus M, Kern D. A hierarchy of timescales in protein dynamics is linked to enzyme catalysis. Nature 2007;450(7171):913–6. [3] Kamerlin SCL, Warshel A. At the dawn of the 21st century: is dynamics the missing link for understanding enzyme catalysis? Proteins 2009;78(6):1339–75. [4] Micheletti C. Comparing proteins by their internal dynamics: exploring structure–function relationships beyond static structural alignments. Phys Life Rev 2013;10:1–26 [in this issue]. [5] Ramanathan A, Savol A, Langmead CJ, Agarwal PK, Chennubhotla CS. Discovering conformational sub-states relevant to protein function. PLoS ONE 2011;6(1):e15827. [6] Ramanathan A, Agarwal PK. Evolutionarily conserved linkage between enzyme fold, flexibility, and catalysis. PLoS Biol 2011;9(11):e1001193. [7] Agarwal PK, Schultz C, Kalivreteno A, Ghosh B, Sheldon B. Engineering a hyper-catalytic enzyme by photo-activated conformation modulation. J Phys Chem Lett 2012;3:1142–6.