Skip to main content

News about Scitation

In December 2016 Scitation will launch with a new design, enhanced navigation and a much improved user experience.

To ensure a smooth transition, from today, we are temporarily stopping new account registration and single article purchases. If you already have an account you can continue to use the site as normal.

For help or more information please visit our FAQs.

banner image
No data available.
Please log in to see this content.
You have no subscription access to this content.
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.
The full text of this article is not currently available.
1.M. H. Olsson, W. W. Parson, and A. Warshel, “Dynamical contributions to enzyme catalysis: Critical tests of a popular hypothesis,” Chem. Rev. 106, 17371756 (2006).
2.S. C. L. Kamerlin and A. Warshel, “At the dawn of the 21st century: Is dynamics the missing link for understanding enzyme catalysis?,” Proteins: Struct., Funct., Bioinf. 78, 13391375 (2010).
3.A. Warshel, “Energetics of enzyme catalysis,” Proc. Natl. Acad. Sci. U. S. A. 75, 52505254 (1978).
4.A. Warshel, P. K. Sharma, M. Kato, Y. Xiang, H. Liu, and M. H. M. Olsson, “Electrostatic basis for enzyme catalysis,” Chem. Rev. 106, 32103235 (2006).
5.A. T. P. Carvalho, F. Duarte, K. Vavitsas, and S. C. L. Kamerlin, Conformational and Chemical Landscapes of Enzyme Catalysis (CRC Press, 2015).
6.G. Careri, P. Fasella, and E. Gratton, “Enzyme dynamics: The statistical physics approach,” Annu. Rev. Biophys. Bioeng. 8, 6997 (1979).
7.B. Gavish and M. M. Werber, “Viscosity-dependent structural fluctuation in enzyme catalysis,” Biochemistry 18, 12691275 (1979).
8.J. A. McCammon, P. G. Wolynes, and M. Karplus, “Picosecond dynamics of tyrosine side chains in proteins,” Biochemistry 18, 927942 (1979).
9.M. Karplus and J. A. McCammon, “Dynamics of proteins: Elements and function,” Annu. Rev. Biochem. 52, 263300 (1983).
10.W. R. Cannon, S. F. Singleton, and S. J. Benkovic, “A perspective on biological catalysis,” Nat. Struct. Biol. 3, 821833 (1996).
11.E. Neria and M. Karplus, “Molecular dynamics of an enzyme reaction: Proton transfer in TIM,” Chem. Phys. Lett. 267, 2330 (1997).
12.D. Antoniou and S. D. Schwartz, “Large kinetic isotope effects in enzymatic proton transfer and the role of substrate oscillations,” Proc. Natl. Acad. Sci. U. S. A. 94, 1236012365 (1997).
13.G. P. Miller and S. J. Benkovic, “Deletion of a highly motional residue affects formation of the Michaelis complex for Escherichia coli dihydrofolate reductase,” Biochemistry 37, 63276335 (1998).
14.P. Zavodszky, J. Kardos, A. Svingor, and G. A. Petsko, “Adjustment of conformational flexibility is a key event in the thermal adaptation of proteins,” Proc. Natl. Acad. Sci. U. S. A. 95, 74067411 (1998).
15.A. Kohen, R. Cannio, S. Bartolucci, and J. P. Klinman, “Enzyme dynamics and hydrogen tunnelling in a thermophilic alcohol dehydrogenase,” Nature 399, 496499 (1999).
16.A. Kohen and J. P. Klinman, “Hydrogen tunneling in biology,” Chem. Biol. 6, R191R198 (1999).
17.X. S. Xie and H. P. Lu, “Single-molecule enzymology,” J. Biol. Chem. 274, 1596715970 (1999).
18.J. Basran, M. J. Sutcliffe, and N. S. Scrutton, “Enzymatic H-transfer requires vibration-driven extreme tunneling,” Biochemistry 38, 32183222 (1999).
19.J. L. Radkiewicz and C. L. Brooks, “Protein dynamics in enzymatic catalysis: Exploration of dihydrofolate reductase,” J. Am. Chem. Soc. 122, 225231 (2000).
20.E. Z. Eisenmesser, D. A. Bosco, M. Akke, and D. Kern, “Enzyme dynamics during catalysis,” Science 295, 15201523 (2002).
21.R. M. Daniel, R. V. Dunn, J. L. Finney, and J. C. Smith, “The role of dynamics in enzyme activity,” Annu. Rev. Biophys. Biomol. Struct. 32, 6992 (2003).
22.K. Nam, X. Prat-Resina, M. Garcia-Viloca, L. S. Devi-Kesavan, and J. Gao, “Dynamics of an enzymatic substitution reaction in haloalkane dehalogenase,” J. Am. Chem. Soc. 126, 13691376 (2004).
23.A. Warshel, Computer Modeling of Chemical Reactions in Enzymes and Solutions (John Wiley & Sons, New York, 1991).
24.I. F. Thorpe, “Barriers to hydride transfer in wild type and mutant dihydrofolate reductase from E. coli,” J. Phys. Chem. B 107, 1404214051 (2003).
25.S. R. Billeter, S. P. Webb, P. K. Agarwal, T. Iordanov, and S. Hammes-Schiffer, “Hydride transfer in liver alcohol dehydrogenase: Quantum dynamics, kinetic isotope effects, and role of enzyme motion,” J. Am. Chem. Soc. 123, 1126211272 (2001).
26.A. Warshel, “Dynamics of enzymatic reactions,” Proc. Natl. Acad. Sci. U. S. A. 81, 444448 (1984).
27.A. Warshel and W. W. Parson, “Dynamics of biochemical and biophysical reactions: Insight from computer simulations,” Q. Rev. Biophys. 34, 563670 (2001).
28.A. Warshel, F. Sussman, and J.-K. Hwang, “Evaluation of catalytic free energies in genetically modified proteins,” J. Mol. Biol. 201, 139159 (1988).
29.J. Villà and A. Warshel, “Energetics and dynamics of enzymatic reactions,” J. Phys. Chem. B 105, 78877907 (2001).
30.D. Kern and E. R. Zuiderweg, “The role of dynamics in allosteric regulation,” Curr. Opin. Struct. Biol. 13, 748757 (2003).
31.M. Wolf-Watz, V. Thai, K. Henzler-Wildman, G. Hadjipavlou, E. Z. Eisenmesser, and D. Kern, “Linkage between dynamics and catalysis in a thermophilic-mesophilic enzyme pair,” Nat. Struct. Mol. Biol. 11, 945949 (2004).
32.D. Kern, E. Z. Eisenmesser, and M. Wolf-Watz, “Enzyme dynamics during catalysis measured my NMR spectroscopy,” Methods Enzymol. 394, 507524 (2005).
33.E. Z. Eisenmesser, O. Millet, W. Labeikovsky, D. M. Korzhnev, M. Wolf-Watz, D. A. Bosco, J. J. Skalicky, and L. E. Kay, “Intrinsic dynamics of an enzyme underlies catalysis,” Nature 438, 117121 (2005).
34.K. Henzler-Wildman and D. Kern, “Dynamic personalities of proteins,” Nature 450, 964972 (2007).
35.K. A. Henzler-Wildman, M. Lei, V. Thai, S. J. Kerns, M. Karplus, and D. Kern, “A hierarchy of timescales in protein dynamics is linked to enzyme catalysis,” Nature 450, 913916 (2007).
36.K. A. Henzler-Wildman, V. Thai, M. Lei, M. Ott, M. Wolf-Watz, T. Fenn, E. Pozharski, M. A. Wilson, G. A. Petsko, M. Karplus, C. G. Hubner, and D. Kern, “Intrinsic motions along an enzymatic reaction trajectory,” Nature 450, 838844 (2007).
37.S. Kale, G. Ulas, J. Song, G. W. Brudvig, W. Furey, and F. Jordan, “Efficient coupling of catalysis and dynamics in the E1 component of Escherichia coli pyruvate dehydrogenase multienzyme complex,” Proc. Natl. Acad. Sci. U. S. A. 105, 11581163 (2008).
38.S. Saen-Oon, M. Ghanem, V. L. Schramm, and S. D. Schwart, “Remote mutations and active site dynamics correlate with catalytic properties of purine nucleoside phosphorylase,” Biophys. J. 94, 40784088 (2008).
39.L. R. Masterson, C. Cheng, T. Yu, M. Tonelli, A. Kornev, S. S. Taylos, and G. Veglia, “Dynamics connect substrate recognition to catalysis in protein kinase A,” Nat. Chem. Biol. 6, 821828 (2010).
40.G. Bhabha, J. Lee, D. C. Ekiert, J. Gam, I. A. Wilson, H. J. Dyson, S. J. Benkovic, and P. E. Wright, “A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis,” Science 332, 234238 (2011).
41.J. P. Klinman and A. Kohen, “Hydrogen tunneling links protein dynamics to enzyme catalysis,” Annu. Rev. Biochem. 82, 471496 (2013).
42.P. Singh, K. Francis, and A. Kohen, “Network of remote and local protein dynamics in dihydrofolate reductase catalysis,” ACS Catal. 5, 30673073 (2015).
43.J. Villali and D. Kern, “Choreographing an enzyme’s dance,” Curr. Opin. Chem. Biol. 14, 636643 (2010).
44.A. Warshel and Z. T. Chu, “Quantum corrections for rate constants of diabatic and adiabatic reactions in solutions,” J. Chem. Phys. 93, 40034015 (1990).
45.J.-K. Hwang, Z. T. Chu, A. Yadav, and A. Warshel, “Simulations of quantum mechanical corrections for rate constants of hydride-transfer reactions in enzymes and solutions,” J. Phys. Chem. 95, 84458448 (1991).
46.S. C. Sharma and J. P. Klinman, “Experimental evidence for hydrogen tunneling when the isotopic Arrhenius prefactor (AH/AD) is unity,” J. Am. Chem. Soc. 130, 1763217633 (2008).
47.A. Shurki and A. Warshel, “Structure/function correlations of proteins using MM, QM/MM, and related approaches: Methods, concepts, pitfalls, and current progress,” Adv. Protein Chem. 66, 249313 (2003).
48.C. H. Bennett, “Molecular dynamics and transition state theory: The simulation of infrequent events,” in Algorithms for Chemical Computations, edited by R. E. Christofferson (ACS, Washington, DC, 1977), pp. 6397.
49.J. C. Keck, “Variational theory of reaction rates,” Adv. Chem. Phys. 13, 85121 (1966).
50.E. K. Grimmelmann, J. C. Tully, and E. Helfand, “Molecular-dynamics of infrequent events—Thermal-desorption of xenon from a platinum surface,” J. Chem. Phys. 74, 53005310 (1981).
51.A. Warshel and M. Levitt, “Theoretical studies of enzymic reactions: Dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme,” J. Mol. Biol. 103, 227249 (1976).
52.D. Chandler, “Statistical-mechanics of isomerization dynamics in liquids and transition-state approximation,” J. Chem. Phys. 68, 29592970 (1978).
53.R. O. Rosenberg, B. J. Berne, and D. Chandler, “Isomerization dynamics in liquids by molecular dynamics,” Chem. Phys. Lett. 75, 162168 (1980).
54.J. B. Anderson, “Predicting rare events in molecular dynamics,” Adv. Chem. Phys. 91, 381431 (1995).
55.L. Y. P. Luk, J. J. Ruiz-Pernia, W. M. Dawson, M. Roca, E. J. Loveridge, D. R. Glowacki, J. N. Harvey, A. J. Mulholland, I. Tunon, V. Moliner, and R. K. Allemann, “Unraveling the role of protein dynamics in dihydrofolate reductase catalysis,” Proc. Natl. Acad. Sci. U. S. A. 110, 1634416349 (2013).
56.H. Liu and A. Warshel, “The catalytic effect of dihydrofolate reductase and its mutants is determined by reorganization energies,” Biochemistry 46, 60116025 (2007).
57.A. Warshel, “Molecular dynamics simulations of biological reactions,” Acc. Chem. Res. 35, 385395 (2002).
58.D. D. Boehr, H. J. Dyson, and P. E. Wright, “An NMR perspective on enzyme dynamics,” Chem. Rev. 106, 30553079 (2006).
59.M. H. M. Olsson and A. Warshel, “Solute solvent dynamics and energetics in enzyme catalysis: The SN2 reaction of dehalogenase as a general benchmark,” J. Am. Chem. Soc. 126, 1516715179 (2004).
60.A. G. Palmer, C. D. Kroenke, and J. P. Loria, “Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules,” Methods Enzymol. 339, 204238 (2001).
61.A. G. Palmer, “NMR characterization of the dynamics of biomacromolecules,” Chem. Rev. 104, 36233640 (2004).
62.M. Akke, “NMR methods for characterizing microsecond to millisecond dynamics in recognition and catalysis,” Curr. Opin. Struct. Biol. 12, 642647 (2002).
63.T. I. Igumenova, K. K. Frederick, and J. A. Wand, “Characterization of the fast dynamics of protein amino acid side chains using NMR relaxation in solution,” Chem. Rev. 106, 16721699 (2006).
64.V. A. Jarymowycz and M. J. Stone, “Fast time scale dynamics of protein backbones: NMR relaxation methods, applications, and functional consequences,” Chem. Rev. 106, 16241671 (2006).
65.U. Brath, M. Akke, D. Yang, L. E. Kay, and F. A. A. Mulder, “Functional dynamics of human FKBP12 revealed by methyl 13C rotating frame relaxation dispersion NMR spectroscopy,” J. Am. Chem. Soc. 128, 57185727 (2006).
66.E. T. Oljeniczak, M.-M. Zhou, and S. W. Fesik, “Changes in the NMR-derived motional parameters of the insulin receptor substrate 1 phosphotyrosine binding domain upon binding of an interleukin 4 receptor phosphopeptide,” Biochemistry 36, 41184124 (1997).
67.A. L. Lee, S. A. Kinnear, and A. J. Wand, “Redistribution and loss of side chain entropy upon formation of a calmodulin-peptide complex,” Nat. Struct. Biol. 7, 7277 (2000).
68.J. J. Falke, “A moving story,” Science 295, 14801481 (2002).
69.G. H. Li and Q. Cui, “What is so special about Arg 55 in the catalysis of cyclophilin A? Insights from hybrid QM/MM simulations,” J. Am. Chem. Soc. 125, 1502815038 (2003).
70.U. Doshi, L. C. McGowan, S. T. Ladani, and D. Hamelberg, “Resolving the complex role of enzyme conformational dynamics in catalytic function,” Proc. Natl. Acad. Sci. U. S. A. 109, 56995704 (2012).
71.D. M. Epstein, S. J. Benkovic, and P. E. Wright, “Dynamics of the dihydrofolate reductase folate complex—Catalytic sites and regions known to undergo conformational change exhibit diverse dynamical features,” Biochemistry 34, 1103711048 (1995).
72.J. R. Schnell, H. J. Dyson, and P. E. Wright, “Structure, dynamics, and catalytic function of dihydrofolate reductase,” Annu. Rev. Biophys. Biomol. Struct. 33, 119140 (2004).
73.A. J. Adamczyk, J. Cao, S. C. Kamerlin, and A. Warshel, “Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions,” Proc. Natl. Acad. Sci. USA 108, 1411514120 (2011).
74.E. J. Loveridge, E. M. Behiry, J. Guo, and R. K. Allemann, “Evidence that a ‘dynamic knockout’ in Escherichia coli dihydrofolate reductase does not affect the chemical step of catalysis,” Nat. Chem. 292297 (2012).
75.Y. Fan, A. Cembran, S. Ma, and J. Gao, “Connecting protein conformational dynamics with catalytic function as illustrated in dihydrofolate reductase,” Biochemistry 52, 20362049 (2013).
76.N. Boekelheide, R. Salomon-Ferrer, and T. F. Miller, “Dynamics and dissipation in enzyme catalysis,” Proc. Natl. Acad. Sci. U. S. A. 108, 1615916163 (2011).
77.M. Akke, “Out of hot water,” Nat. Struct. Mol. Biol. 11, 912913 (2004).
78.R. H. Austin, K. W. Beeson, L. Eisenstein, H. Frauenfelder, and I. C. Gunsalus, “Dynamics of ligand binding to myoglobin,” Biochemistry 14, 53555373 (1979).
79.H. P. Lu, L. Xun, and X. S. Xie, “Single-molecule enzymatic dynamics,” Science 282, 18771882 (1998).
80.A. V. Pisliakov, J. Cao, S. C. Kamerlin, and A. Warshel, “Enzyme millisecond conformational dynamics do not catalyze the chemical step,” Proc. Natl. Acad. Sci. U. S. A. 106, 1735917364 (2009).
81.S. C. L. Kamerlin and A. Warshel, “Multiscale modeling of biological functions,” Phys. Chem. Chem. Phys. 13, 1040110411 (2011).
82.B. R. Prasad, S. C. L. Kamerlin, J. Florián, and A. Warshel, “Prechemistry barriers and checkpoints do not contribute to fidelity and catalysis as long as they are not rate limiting,” Theor. Chem. Acc. 131, 1288 (2012).
83.B. R. Prasad and A. Warshel, “Prechemistry versus preorganization in DNA replication fidelity,” Proteins: Struct. Funct. Bioinf. 79, 29002919 (2011).
84.S. Kirmizialtin, K. A. Johnson, and R. Elber, “Enzyme selectivity of HIV reverse transcriptase: Conformations, ligands and free energy partition,” J. Phys. Chem. B 119, 1151311526 (2015).
85.T. H. Rod, J. L. Radkiewicz, and C. L. Brooks, “Correlated motion and the effect of distal mutations in dihydrofolate reductase,” Proc. Natl. Acad. Sci. U. S. A. 100, 69806985 (2003).
86.S. Hammes-Schiffer, “Quantum-classical simulation methods for hydrogen transfer in enzymes: A case study of dihydrofolate reductase,” Curr. Opin. Struct. Biol. 14, 192201 (2004).
87.J. B. Watney, P. K. Agarwal, and S. Hammes-Schiffer, “Effect of mutation on enzyme motion in dihydrofolate reductase,” J. Am. Chem. Soc. 125, 37453750 (2003).
88.M. I. Franco, L. Turin, A. Mershin, and E. M. C. Skoulakis, “Molecular vibration-sensing component in Drosophila melanogaster olfaction,” Proc. Natl. Acad. Sci. U. S. A. 108, 37973802 (2011).
89.T. P. Hettinger, “Olfaction is a chemical sense, not a spectral sense,” Proc. Natl. Acad. Sci. U. S. A. 108, E349 (2011).
90.A. Warshel and J. K. Hwang, “Simulation of the dynamics of electron transfer reactions in polar solvent: Semiclassical trajectories and dispersed polaron approaches,” J. Chem. Phys. 84, 49384957 (1986).
91.D. Antoniou, S. Caratzoulas, C. Kalyanaraman, J. S. Mincer, and S. D. Schwartz, “Barrier passage and protein dynamics in enzymatically catalyzed reactions,” Eur. J. Biochem. 269, 31033112 (2002).
92.J. E. Basner and S. D. Schwartz, “Donor-acceptor distance and protein promoting vibration coupling to hydride transfer: A possible mechanism for kinetic control in isozymes of human lactate dehydrogenase,” J. Phys. Chem. B 108, 444451 (2004).
93.S. Nunez, D. Antoniou, V. L. Schramm, and S. D. Schwartz, “Promoting vibrations in human purine nucleoside phosphorylase. A molecular dynamics and hybrid quantum mechanical/molecular mechanical study,” J. Am. Chem. Soc. 126, 1572015729 (2004).
94.A. Warshel, “Dynamics of reactions in polar-solvents—Semi-classical trajectory studies of electron-transfer and proton-transfer reactions,” J. Phys. Chem. 86, 22182224 (1982).
95.M. J. Knapp, K. Rickert, and J. P. Klinman, “Temperature-dependent isotope effects in soybean lipoxygenase-1: Correlating hydrogen tunneling with protein dynamics,” J. Am. Chem. Soc. 124, 38653874 (2002).
96.S. Hay and N. S. Scrutton, ”Good vibrations in enzyme-catalyzed reactions,” Nat. Chem. 4(3), 161168 (2012).
97.S. C. L. Kamerlin, J. Mavri, and A. Warshel, “Examining the case for the effect of barrier compression on tunneling, vibrationally enhanced catalysis, catalytic entropy and related issues,” FEBS Lett. 584, 27592766 (2010).
98.M. Roca, H. Liu, B. Messer, and A. Warshel, “On the relationship between thermal stability and catalytic power of enzymes,” Biochemistry 46, 1507615088 (2007).
99.B. Peters, “Transition-state theory dynamics and narrow time scale separation in the rate-promoting vibration model of enzyme catalysis,” J. Chem. Theory Comput. 6, 14471454 (2010).
100.S. Hay, L. O. Johannissen, M. J. Sutcliffe, and N. S. Scrutton, “Barrier compression and its contribution to both classical and quantum mechanical aspects of enzyme catalysis,” Biophys. J. 98, 121128 (2010).
101.J. Y. Zhang and J. P. Klinman, “Enzymatic methyl transfer: Role of an active site residue in generating active site compaction that correlates with catalytic efficiency,” J. Am. Chem. Soc. 133, 17134 (2011).
102.J. Lameira, R. P. Bora, Z. T. Chu, and A. Warshel, “Methyltransferases do not work by compression, cratic, or desolvation effects, but by electrostatic preorganization,” Proteins: Struct. Funct. Bioinf. 83, 318330 (2015).
103.M. Roca, S. Martí, J. Andrés, V. Moliner, I. Tuñón, J. Bertrán, and I. H. Williams, “Theoretical modeling of enzyme catalytic power: Analysis of “cratic” and electrostatic factors in catechol O-methyltransferase,” J. Am. Chem. Soc. 125, 77267737 (2003).
104.J. Zhang, H. J. Kulik, T. J. Martinez, and J. P. Klinman, “Mediation of donor–acceptor distance in an enzymatic methyl transfer reaction,” Proc. Natl. Acad. Sci. U. S. A. 112, 79547959 (2015).
105.M. Štrajbl, A. Shurki, M. Kato, and A. Warshel, “Apparent NAC effect in chorismate mutase reflects electrostatic transition state stabilization,” J. Am. Chem. Soc. 125, 1022810237 (2003).
106.M. J. Knapp and J. P. Klinman, “Environmentally coupled hydrogen tunneling—Linking catalysis to dynamics,” Eur. J. Biochem. 269, 31133121 (2002).
107.X.-Z. Liang and J. P. Klinman, “Structural bases for hydrogen tunneling in enzymes: Progress and puzzles,” Curr. Opin. Struct. Biol. 14, 648655 (2004).
108.S. J. Benkovic, G. G. Hammes, and S. Hammes-Schiffer, “Free-energy landscape of enzyme catalysis,” Biochemistry 47, 33173321 (2008).
109.M. K. Prakash and R. A. Marcus, “An interpretation of fluctuations in enzyme catalysis rate, spectral diffusion, and radiative component of lifetimes in terms of electric field fluctuations,” Proc. Natl. Acad. Sci. U. S. A. 104, 1598215987 (2007).
110.C. A. Arnaud, “Enzymes’ many movements,” Chem. Eng. News 87, 3436 (2009).
111.S. Kumar, B. Y. Ma, C. J. Tsai, N. Sinha, and R. Nussinov, “Folding and binding cascades: Dynamic landscapes and population shifts,” Protein Sci. 9, 1019 (2000).
112.W. Min, S. Xie, and B. Bagchi, “Two-dimensional reaction free energy surfaces of catalytic reaction: Effects of protein conformational dynamics on enzyme catalysis,” J. Phys. Chem. B 112, 454466 (2008).
113.Y. Xiang, M. F. Goodman, W. A. Beard, S. H. Wilson, and A. Warshel, “Exploring the role of large conformational changes in the fidelity of DNA polymerase β,” Proteins 70, 231247 (2008).
114.M. Roca, B. Messer, D. Hilvert, and A. Warshel, “On the relationship between folding and chemical landscapes in enzyme catalysis,” Proc. Natl. Acad. Sci. U. S. A. 105, 1387713882 (2008).
115.J. Florián, M. F. Goodman, and A. Warshel, “Computer simulations of protein functions: Searching for the molecular origin of the replication fidelity of DNA polymerases,” Proc. Natl. Acad. Sci. U. S. A. 102, 68196824 (2005).
116.K. Vamvaca, B. Vögeli, P. Kast, K. Pervushin, and D. Hilvert, “An enzymatic molten globule: Efficient coupling of folding and catalysis,” Proc. Natl. Acad. Sci. U. S. A. 101, 1286012864 (2004).
117.K. Pervushin, K. Vamvaca, B. Vögeli, and D. Hilvert, “Structure and dynamics of a molten globular enzyme,” Nat. Struct. Mol. Biol. 14, 12021206 (2007).
118.Z. Nagel and J. P. Klinman, “Tunneling and dynamics in enzymatic hydride transfer,” Chem. Rev. 106, 30953118 (2006).
119.J. P. Klinman, “An integrated model for enzyme catalysis emerges from studies of hydrogen tunneling,” Chem. Phys. Lett. 471, 179193 (2009).
120.J. Villà, M. Štrajbl, T. M. Glennon, Y. Y. Sham, Z. T. Chu, and A. Warshel, “How important are entropy contributions in enzymatic catalysis?,” Proc. Natl. Acad. Sci. U. S. A. 97, 1189911904 (2000).
121.P. Schopf, M. J. L. Mills, and A. Warshel, “The entropic contributions in vitamin B-12 enzymes still reflect the electrostatic paradigm,” Proc. Natl. Acad. Sci. U. S. A. 112, 43284333 (2015).
122.D. Ringe and G. A. Petsko, “Quantum enzymology—Tunnel vision,” Nature 399, 417418 (1999).
123.A. Kohen and J. P. Klinman, “Protein flexibility correlates with degree of hydrogen tunneling in thermophilic and mesophilic alcohol dehydrogenases,” J. Am. Chem. Soc. 122, 1073810739 (2000).
124.G. P. Miller and S. J. Benkovic, “Stretching excercises—Flexibility in dihydrofolate reductase catalysis,” Chem. Biol. 5, R105R113 (1998).
125.P. T. Rajagopalan and S. J. Benkovic, “Preorganization and protein dynamics in enzyme catalysis,” Chem. Rec. 2, 2436 (2002).
126.G. G. Dodson, D. P. Lane, and C. S. Verma, “Molecular simulations of protein dynamics: New windows on mechanisms in biology,” EMBO Rep. 9, 144150 (2008).
127.G. Maglia, M. H. Javed, and R. K. Allemann, “Hydride transfer during catalysis by dihydrofolate reductase from Thermotoga maritima,” Biochem. J. 374, 529535 (2003).
128.A. Wrba, A. Schwieger, V. Schultes, R. Jaenicke, and P. Zavodsky, “Extremely thermostable D-glyceraldehyde-3-phosphate dehydrogenase from the eubacterium Thermotoga maritima,” Biochemistry 29, 75847592 (1990).
129.M. Ben-David, J. L. Sussman, C. I. Maxwell, K. Szeler, S. C. L. Kamerlin, and D. S. Tawfik, “Catalytic stimulation by restrained active-site floppiness—The case of high density lipoprotein-bound serum paraoxonase-1,” J. Mol. Biol. 427, 13591374 (2015).
130.G. V. Isaksen, J. Aqvist, and B. O. Brandsdal, “Protein surface softness is the origin of enzyme cold-adaptation of trypsin,” PLoS Comp. Biol. 10, e1003813 (2014).
131.P. F. Cook, Enzyme Mechanism from Isotope Effects (CRC Press, Boca Raton, Florida, 1991).
132.A. Kohen and H. Limbarch, Isotopic Effects in Chemistry and Biology (Taylor & Francis Group, LLC, Boca Raton, 2006).
133.J. P. Klinman, “Linking protein structure and dynamics to catalysis: The role of hydrogen tunneling,” Philos. Trans. R. Soc., B. 361, 13231331 (2006).
134.S.-C. Tsai and J. P. Klinman, “Probes of hydrogen tunneling with horse liver alcohol dehydrogenase at subzero temperature,” Biochemistry 40, 23032311 (2001).
135.B. J. Bahnson, T. D. Colby, J. K. Chin, B. M. Goldstein, and J. P. Klinman, “A link between protein structure and enzyme catalyzed hydrogen tunneling,” Proc. Natl. Acad. Sci. U. S. A. 94, 1279712802 (1997).
136.K. L. Grant and J. P. Klinman, “Evidence that both protium and deuterium undergo significant tunneling in the reaction catalyzed by bovine serum amine oxidase,” Biochemistry 28, 65976605 (1989).
137.T. Jonsson, M. H. Glickman, S. J. Sun, and J. P. Klinman, “Experimental evidence for extensive tunneling of hydrogen in the lipoxygenase reaction: Implications for enzyme catalysis,” J. Am. Chem. Soc. 118, 1031910320 (1996).
138.A. Kohen, T. Jonsson, and J. P. Klinman, “Effects of protein glycosylation on catalysis: Changes in hydrogen tunneling and enthalpy of activation in the glucose oxidase reaction,” Biochemistry 36, 6854 (1997).
139.S. Hay and N. S. Scrutton, “Good vibrations in enzyme-catalysed reactions,” Nat Chem 4, 161168 (2012).
140.P. Ball, “Enzymes: By chance, or by design?,” Nature 431, 396397 (2004).
141.J. K. Hwang and A. Warshel, “How important are quantum mechanical nuclear motions in enzyme catalysis?,” J. Am. Chem. Soc. 118, 1174511751 (1996).
142.M. H. M. Olsson, J. Mavri, and A. Warshel, “Transition state theory can be used in studies of enzyme catalysis: Lessons from simulations of tunnelling and dynamical effects in lipoxygenase and other systems,” Philos. Trans. R. Soc., B 361, 14171432 (2006).
143.H. Liu and A. Warshel, “Origin of the temperature dependence of isotope effects in enzymatic reactions: The case of dihydrofolate reductase,” J. Phys. Chem. B 111, 78527861 (2007).
144.D. T. Major, A. Heroux, A. M. Orville, M. P. Valley, P. F. Fitzpatrick, and J. L. Gao, “Differential quantum tunneling contributions in nitroalkane oxidase catalyzed and the uncatalyzed proton transfer reaction,” Proc. Natl. Acad. Sci. U. S. A. 106, 2073420739 (2009).
145.J. Luo, K. Kahn, and T. C. Bruice, “The linear dependence of log(kcat/Km) for reduction of NAD+ by PhCH2OH on the distance between reactants when catalyzed by horse liver alcohol dehydrogenase and 203 single point mutants,” Bioorg. Chem. 27, 289296 (1999).
146.J. P. Klinman, “Quantum mechanical effects in enzyme-catalysed hydrogen transfer reactions,” Trends Biochem. Sci. 14, 368373 (1989).
147.J. S. Mincer and S. D. Schwartz, “A computational method to identify residues important in creating a protein promoting vibration in enzymes,” J. Phys. Chem. B 107, 366371 (2003).
148.M. J. Sutcliffe and N. S. Scrutton, “Enzymology takes a quantum leap forward,” Philos. Trans. R. Soc., A 358, 367386 (2000).
149.E. Hatcher, A. V. Soudackov, and S. Hammes-Schiffer, “Proton-coupled electron transfer in soybean lipoxygenase: Dynamical behavior and temperature dependence of kinetic isotope effects,” J. Am. Chem. Soc. 129, 187196 (2007).
150.S. C. L. Kamerlin and A. Warshel, “An analysis of all the relevant facts and arguments indicates that enzyme catalysis does not involve large contributions from nuclear tunneling,” J. Phys. Org. Chem. 23, 677684 (2009).
151.A. M. Kuznetsov and J. Ulstrop, “Proton and hydrogen atom tunnelling in hydrolytic and redox enzyme catalysis,” Can. J. Chem. 77, 10851096 (1999).
152.L. Wang, N. M. Goodey, S. J. Benkovic, and A. Kohen, “Coordinated effects of distal mutations on environmentally coupled tunneling in dihydrofolate reductase,” Proc. Natl. Acad. Sci. U. S. A 103, 1575315758 (2006).
153.W. J. Bruno and W. Bialek, “Vibrationally enhanced tunneling as a mechanism for enzymatic hydrogen transfer,” Biophys. J. 63, 689699 (1992).
154.B. M. Dunn and T. C. Bruice, “Physical organic models for the mechanism of lysozyme action,” Adv. Enzymol. Relat. Areas Mol. Biol. 37, 160 (2006).
155.T. H. Fife, S. H. Jaffe, and R. Natarajan, “Intramolecular general acid and electrostatic catalysis in acetal hydrolysis. Hydrolysis of 2-(substituted phenoxy)-6-carboxytetrahydropyrans and 2-alkoxy-6-carboxytetrahydropyrans,” J. Am. Chem. Soc. 113, 76467653 (1991).
156.W. P. Jencks, “Binding energy, specificity, and enzymic catalysis: The circe effect,” in Advances in Enzymology and Related Areas of Molecular Biology, edited by A. Meister (J. Wiley & Sons, Inc., New York, 1975), Vol. 43, pp. 219410.
157.A. Barrozo, F. Duarte, P. Bauer, A. T. P. Carvalho, and S. C. L. Kamerlin, “Cooperative electrostatic interactions drive functional evolution in the alkaline phosphatase superfamily,” J. Am. Chem. Soc. 137, 90619076 (2015).
158.Z. D. Nagel and J. P. Klinman, “A 21st century revisionist’s view at a turning point in enzymology,” Nat. Chem. Biol. 5, 543550 (2009).
159.S. D. Fried, S. Bagchi, and S. G. Boxer, “Extreme electric fields power catalysis in the active site of ketosteroid isomerase,” Science 346, 15101514 (2014).
160.A. Warshel, “Multiscale modeling of biological functions: From enzymes to molecular machines (Nobel Lecture),” Angw. Chem. Int. Ed. 53, 1002010031 (2014).
161.S. C. L. Kamerlin, M. Haranczyk, and A. Warshel, “Progress in ab initio QM/MM free-energy simulations of electrostatic energies in proteins: Accelerated QM/MM studies of pKa, redox reactions, and solvation free energies,” J. Phys. Chem. B 113, 12531272 (2009).
162.E. Rosta, M. Klähn, and A. Warshel, “Towards accurate ab initio QM/MM calculations of free-energy profiles of enzymatic reactions,” J. Phys. Chem. B 110, 29342941 (2006).
163.M. Štrajbl, G. Hong, and A. Warshel, “Ab initio QM/MM simulation with proper sampling: ‘First principle’ calculations of the free energy of the autodissociation of water in aqueous solution,” J. Phys. Chem. B 106, 1333313343 (2002).
164.N. V. Plotnikov and A. Warshel, “Exploring, refining, and validating the paradynamics QM/MM sampling,” J. Phys. Chem. B 116, 1034210356 (2012).
165.S. C. L. Kamerlin and A. Warshel, “The EVB as a quantitative tool for formulating simulations and analyzing biological and chemical reactions,” Faraday Discuss. 145, 71106 (2010).
166.R. A. Kuharski, J. S. Bader, D. Chandler, M. Sprik, M. L. Klein, and R. W. Impey, “Molecular model for aqueous Ferrous-Ferric electron transfer,” J. Chem. Phys. 89, 32483257 (1988).
167.M. Cascella, A. Magistrato, I. Tavernelli, P. Carloni, and U. Rothlisberger, “Role of protein frame and solvent for the redox properties of azurin from Pseudonomas aeruginosa,” Proc. Natl. Acad. Sci. U. S. A. 103, 1964119646 (2006).
168.J. Blumberger, L. Bernasconi, I. Tavernelli, R. Vuilleumier, and M. Sprik, “Electronic structure and solvation of copper and silver ions: A theoretical picture of a model aqueous redox reaction,” J. Am. Chem. Soc. 126, 39283938 (2004).
169.Y. Kim, J. C. Corchado, J. Villà, J. Xing, and D. G. Truhlar, “Multiconfiguration molecular mechanics algorithm for potential energy surfaces of chemical reactions,” J. Chem. Phys. 112, 27182735 (2000).
170.J. Florián, “Comment on molecular mechanics for chemical reactions,” J. Phys. Chem. A 106, 50465047 (2002).
171.M. Higashi and D. G. Truhlar, “Electrostatically embedded multiconfiguration molecular mechanics based on the combined density functional and molecular mechanical method,” J. Chem. Theor. Comput. 4, 790803 (2008).
172.M. P. Frushicheva, J. Cao, Z. T. Chu, and A. Warshel, “Exploring challenges in rational enzyme design by simulating the catalysis in artificial Kemp eliminase,” Proc. Natl. Acad. Sci. U. S. A. 107, 1686916874 (2010).
173.M. P. Frushicheva, J. Cao, and A. Warshel, “Challenges and advances in validating enzyme design proposals: The case of Kemp eliminase catalysis,” Biochemistry 50, 38493858 (2011).
174.M. P. Frushicheva, M. J. L. Mills, P. Schopf, M. K. Singh, R. B. Prasad, and A. Warshel, “Computer aided enzyme design and catalytic concepts,” Curr. Opin. Chem. Biol. 21, 5662 (2014).
175.S. Hammes-Schiffer and S. J. Benkovic, “Relating protein motion to catalysis,” Annu. Rev. Biochem. 75, 519541 (2006).
176.S. C. L. Kamerlin and A. Warshel, “Reply to Karplus: Conformational dynamics have no role in the chemical step,” Proc. Natl. Acad. Sci. U. S. A. 107, E72 (2010).
177.A. Kohen, “Role of dynamics in enzyme catalysis: Substantial versus semantic controversies,” Acc. Chem. Res. 48, 466473 (2015).
178.J. K. Lassila, “Conformational diversity and computational enzyme design,” Curr. Opin. Chem. Biol. 14, 676682 (2010).
179.S. M. C. Gobeil, C. M. Clouthier, J. Park, D. Gagne, A. M. Berghuis, N. Doucet, and J. N. Pelletier, “Maintenance of native-like protein dynamics may not be required for engineering functional proteins,” Chem. Biol. 21, 13301340 (2014).
180.N. Tokuriki and C. J. Jackson, “Enzyme dynamics and engineering: One step at a time,” Chem. Biol. 21, 12591260 (2014).
181.A. Bar-Even, R. Milo, E. Noor, and D. S. Tawfik, “The moderately efficient enzyme: Futile encounters and enzyme floppiness,” Biochemistry 54, 49694977 (2015).
182.R. García-Meseguer, S. Martí, J. J. Ruiz-Pernía, V. Moliner, and I. Tuñón, “Studying the role of protein dynamics in an SN2 enzyme reaction using free-energy surfaces and solvent coordinates,” Nat. Chem. 5, 566571 (2013).
183.D. R. Glowacki, J. N. Harvey, and A. J. Mulholland, “Taking Ockham’s razor to enzyme dynamics and catalysis,” Nature Chem. 4, 169176 (2012).
184.I. Tunon, D. Laage, and J. T. Hynes, “Are there dynamical effects in enzyme catalysis? Some thoughts concerning the enzymatic chemical step,” Arch. Biochem. Biophys. 582, 4255 (2015).

Data & Media loading...


Article metrics loading...



Enzymes control chemical reactions that are key to life processes, and allow them to take place on the time scale needed for synchronization between the relevant reaction cycles. In addition to general interest in their biological roles, these proteins present a fundamental scientific puzzle, since the origin of their tremendous catalytic power is still unclear. While many different hypotheses have been put forward to rationalize this, one of the proposals that has become particularly popular in recent years is the idea that dynamical effects contribute to catalysis. Here, we present a critical review of the dynamical idea, considering all reasonable definitions of what does and does not qualify as a dynamical effect. We demonstrate that no dynamical effect (according to these definitions) has ever been experimentally shown to contribute to catalysis. Furthermore, the existence of non-negligible dynamical contributions to catalysis is not supported by consistent theoretical studies. Our review is aimed, in part, at readers with a background in chemical physics and biophysics, and illustrates that despite a substantial body of experimental effort, there has not yet been any study that consistently established a connection between an enzyme’s conformational dynamics and a significant increase in the catalytic contribution of the chemical step. We also make the point that the dynamical proposal is not a semantic issue but a well-defined scientific hypothesis with well-defined conclusions.


Full text loading...


Access Key

  • FFree Content
  • OAOpen Access Content
  • SSubscribed Content
  • TFree Trial Content
752b84549af89a08dbdd7fdb8b9568b5 journal.articlezxybnytfddd