A. M. Klibanov, Improving Enzymes by Using Them in Organic Solvents, Nature, vol.409, issue.6817, pp.241-246, 2001.
DOI : 10.1038/35051719

M. J. Liszka, M. E. Clark, E. Schneider, and D. S. Clark, Nature Versus Nurture: Developing Enzymes That Function Under Extreme Conditions, Annual Review of Chemical and Biomolecular Engineering, vol.3, issue.1, pp.77-102
DOI : 10.1146/annurev-chembioeng-061010-114239

J. Kraut, Serine Proteases: Structure and Mechanism of Catalysis, Annual Review of Biochemistry, vol.46, issue.1, pp.331-358, 1977.
DOI : 10.1146/annurev.bi.46.070177.001555

L. Hedstrom, Serine Protease Mechanism and Specificity, Chemical Reviews, vol.102, issue.12, pp.4501-4524, 2002.
DOI : 10.1021/cr000033x

C. J. Schofield and J. Hajdu, X-Ray Snapshots of Serine Protease Catalysis Reveal a Tetrahedral Intermediate, Nat. Struct. Biol, vol.8, pp.689-694, 2001.

A. Warshel, G. Naray-szabo, F. Sussman, and J. K. Hwang, How do serine proteases really work?, Biochemistry, vol.28, issue.9, pp.3629-3637, 1989.
DOI : 10.1021/bi00435a001

M. Topf, P. Várnai, and W. G. Richards, Ab Initio QM/MM Dynamics Simulation of the Tetrahedral Intermediate of Serine Proteases:?? Insights into the Active Site Hydrogen-Bonding Network, Journal of the American Chemical Society, vol.124, issue.49, pp.14780-14788, 2002.
DOI : 10.1021/ja026219q

T. Ishida and S. Kato, Theoretical Perspectives on the Reaction Mechanism of Serine Proteases:?? The Reaction Free Energy Profiles of the Acylation Process, Journal of the American Chemical Society, vol.125, issue.39, pp.12035-12048, 2003.
DOI : 10.1021/ja021369m

Y. Zhou, S. Wang, and Y. Zhang, Catalytic Reaction Mechanism of Acetylcholinesterase Determined by BornOppenheimer Ab Initio QM/MM Molecular Dynamics Simulations, J. Phys

Z. Yang and A. J. Russell, Enzymatic Reactions in Organic Media, pp.43-69, 1996.

S. Chatterjee and A. J. Russell, Determination of equilibrium and individual rate constants for subtilisin-catalyzed transesterification in anhydrous environments, Biotechnology and Bioengineering, vol.8, issue.9, pp.1069-1077, 1992.
DOI : 10.1016/0167-4838(90)90080-Y

P. P. Wangikar, T. P. Graycar, D. A. Estell, D. S. Clark, and J. S. Dordick, Protein and solvent engineering of subtilisin BPN' in nearly anhydrous organic media, Journal of the American Chemical Society, vol.115, issue.26, pp.12231-12237, 1993.
DOI : 10.1021/ja00079a001

R. K. Eppler, R. S. Komor, J. Huynh, J. S. Dordick, J. A. Reimer et al., Water dynamics and salt-activation of enzymes in organic media: Mechanistic implications revealed by NMR spectroscopy, Proc. Natl. Acad. Sci, pp.5706-5710, 2006.
DOI : 10.1016/0301-4622(92)80040-C

D. R. Glowacki, J. N. Harvey, and A. J. Mulholland, Taking Ockham's razor to enzyme dynamics and catalysis, Nature Chemistry, vol.85, issue.3, pp.169-176, 2012.
DOI : 10.1021/j150606a003

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, Nature Chemistry, vol.120, issue.7, pp.566-571, 2013.
DOI : 10.1007/s00214-007-0310-x

L. Masgrau and D. G. Truhlar, The Importance of Ensemble Averaging in Enzyme Kinetics, Accounts of Chemical Research, vol.48, issue.2, pp.431-438, 2014.
DOI : 10.1021/ar500319e

J. K. Hwang, G. King, S. Creighton, and A. Warshel, Simulation of free energy relationships and dynamics of SN2 reactions in aqueous solution, Journal of the American Chemical Society, vol.110, issue.16, pp.5297-5311, 1988.
DOI : 10.1021/ja00224a011

K. Ando and J. Hynes, HCl acid ionization in water: A theoretical molecular modeling, Journal of Molecular Liquids, vol.64, issue.1-2, pp.25-37, 1995.
DOI : 10.1016/0167-7322(95)92818-V

W. H. Thompson and J. Hynes, Frequency Shifts in the Hydrogen-Bonded OH Stretch in Halide???Water Clusters. The Importance of Charge Transfer, Journal of the American Chemical Society, vol.122, issue.26, pp.6278-6286, 2000.
DOI : 10.1021/ja993058q

R. Vuilleumier and D. Borgis, An Extended Empirical Valence Bond Model for Describing Proton Mobility in Water, Israel Journal of Chemistry, vol.7, issue.3-4, pp.457-467, 1999.
DOI : 10.1039/a808871c

U. W. Schmitt and G. A. Voth, Multistate Empirical Valence Bond Model for Proton Transport in Water, The Journal of Physical Chemistry B, vol.102, issue.29, pp.5547-5551, 1998.
DOI : 10.1021/jp9818131

D. R. Glowacki, R. A. Rose, S. J. Greaves, A. J. Orr-ewing, and J. N. Harvey, Ultrafast energy flow in the wake of solution-phase bimolecular reactions, Nature Chemistry, vol.132, issue.11, pp.850-855, 2011.
DOI : 10.1021/ja105100f

J. Åqvist and A. Warshel, Simulation of enzyme reactions using valence bond force fields and other hybrid quantum/classical approaches, Chemical Reviews, vol.93, issue.7, pp.2523-2544, 1993.
DOI : 10.1021/cr00023a010

S. Hammes-schiffer and S. R. Billeter, Hybrid approach for the dynamical simulation of proton and hydride transfer in solution and proteins, International Reviews in Physical Chemistry, vol.45, issue.4, pp.591-616, 2001.
DOI : 10.1063/1.482053

S. Hammes-schiffer and A. Soudackov, Proton-Coupled Electron Transfer in Solution, Proteins, and Electrochemistry extdagger, J. Phys. Chem. B, vol.28, issue.112, pp.14108-14123, 2008.

S. C. Kamerlin and A. Warshel, The EVB as a quantitative tool for formulating simulations and analyzing biological and chemical reactions, Faraday Discuss., vol.40, pp.71-106, 2009.
DOI : 10.1021/jp711496y

M. Kazemi, F. Himo, and J. Åqvist, Enzyme catalysis by entropy without Circe effect, Proc. Natl. Acad. Sci. U S A 2016, pp.2406-2417
DOI : 10.1016/j.bpc.2006.12.010

N. V. Plotnikov, S. C. Kamerlin, and A. Warshel, Paradynamics: An Effective and Reliable Model for Ab Initio QM/MM Free-Energy Calculations and Related Tasks, The Journal of Physical Chemistry B, vol.115, issue.24, pp.7950-7962, 2011.
DOI : 10.1021/jp201217b

B. Hartke and S. Grimme, Reactive force fields made simple, Phys. Chem. Chem. Phys., vol.9, issue.26, pp.16715-16723, 2015.
DOI : 10.1021/ct300951j

V. M. Paradkar and J. S. Dordick, Mechanism of extraction of chymotrypsin into isooctane at very low concentrations of aerosol OT in the absence of reversed micelles, Biotechnology and Bioengineering, vol.4, issue.6, pp.529-540, 1994.
DOI : 10.1016/0304-4157(88)90025-1

R. D. Skeel, L. Kale, and K. Schulten, Scalable Molecular Dynamics With NAMD, J. Comput

R. Luo, R. C. Walker, W. Zhang, and K. M. Merz, Amber 12. University of California, 37) MacKerell Jr

M. J. Field, S. Fischer, J. Gao, H. Guo, and S. Ha, All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins, J. Phys. Chem. B, vol.102, pp.3586-3616, 1998.

A. D. Mackerell, M. Feig, and C. L. Brooks, Extending the treatment of backbone energetics in protein force fields: Limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations, Journal of Computational Chemistry, vol.44, issue.Pt 6 Pt 1, pp.1400-1415, 2004.
DOI : 10.1080/07391102.1991.10507873

H. J. Berendsen, J. R. Grigera, and T. P. Straatsma, The missing term in effective pair potentials, The Journal of Physical Chemistry, vol.91, issue.24, pp.6269-6271, 1987.
DOI : 10.1021/j100308a038

S. Abel, F. Sterpone, S. Bandyopadhyay, and M. Marchi, Molecular Modeling and Simulations of AOT???Water Reverse Micelles in Isooctane:?? Structural and Dynamic Properties, The Journal of Physical Chemistry B, vol.108, issue.50
DOI : 10.1021/jp047138e

J. P. Ryckaert, Special geometrical constraints in the molecular dynamics of chain molecules, Molecular Physics, vol.47, issue.3
DOI : 10.1063/1.1701684

S. Miyamoto and P. A. Kollman, Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models, Journal of Computational Chemistry, vol.114, issue.8, pp.952-962, 1992.
DOI : 10.1007/978-94-015-7658-1_21

T. Darden, D. York, and L. Pedersen, ) method for Ewald sums in large systems, The Journal of Chemical Physics, vol.9, issue.12, pp.10089-10092, 1993.
DOI : 10.1126/science.2548279

N. Otte, M. Bocola, and W. Thiel, Force-field parameters for the simulation of tetrahedral intermediates of serine hydrolases, Journal of Computational Chemistry, vol.8, issue.1, pp.154-162, 2009.
DOI : 10.1016/S0166-1280(03)00285-9

A. Warshel, F. Sussman, and J. K. Hwang, Evaluation of catalytic free energies in genetically modified proteins, Journal of Molecular Biology, vol.201, issue.1, pp.139-159, 1988.
DOI : 10.1016/0022-2836(88)90445-7

P. A. Fitzpatrick, A. C. Steinmetz, D. Ringe, and A. M. Klibanov, Enzyme crystal structure in a neat organic solvent., Proc. Natl. Acad. Sci, pp.8653-8657, 1993.
DOI : 10.1073/pnas.90.18.8653

A. D. Boese and J. M. Martin, Development of density functionals for thermochemical kinetics, The Journal of Chemical Physics, vol.121, issue.8, pp.3405-3416, 2004.
DOI : 10.1063/1.453520

W. H. Thompson, Mixed quantum???classical simulation of vibrational frequency modulations of a diatomic molecule in a rare gas fluid, Chemical Physics Letters, vol.350, issue.1-2, pp.113-118, 2001.
DOI : 10.1016/S0009-2614(01)01262-3

J. C. Light, I. P. Hamilton, and J. Lill, Generalized discrete variable approximation in quantum mechanics, The Journal of Chemical Physics, vol.82, issue.3, pp.1400-1409, 1985.
DOI : 10.1021/j150662a018

D. T. Colbert and W. H. Miller, ???matrix Kohn method, The Journal of Chemical Physics, vol.96, issue.3, pp.1982-1991, 1992.
DOI : 10.1063/1.1673259

C. Lanczos, An iteration method for the solution of the eigenvalue problem of linear differential and integral operators, Journal of Research of the National Bureau of Standards, vol.45, issue.4, pp.255-282, 1950.
DOI : 10.6028/jres.045.026

J. P. Bergsma, B. J. Gertner, K. R. Wilson, and J. Hynes, 2 reaction in water, The Journal of Chemical Physics, vol.26, issue.3, pp.1356-1376, 1987.
DOI : 10.1073/pnas.80.14.4315

E. A. Carter, G. Ciccotti, J. T. Hynes, and R. Kapral, Constrained reaction coordinate dynamics for the simulation of rare events, Chemical Physics Letters, vol.156, issue.5, pp.472-477, 1989.
DOI : 10.1016/S0009-2614(89)87314-2

V. Daggett, S. Schroeder, and P. Kollman, Catalytic pathway of serine proteases: classical and quantum mechanical calculations, Journal of the American Chemical Society, vol.113, issue.23, pp.8926-8935, 1991.
DOI : 10.1021/ja00023a047

B. J. Gertner, J. P. Bergsma, K. R. Wilson, S. Lee, and J. Hynes, 2 reactions in polar solvents, The Journal of Chemical Physics, vol.86, issue.3, pp.1377-1386, 1987.
DOI : 10.1063/1.1742723

I. Tuñón, D. Laage, and J. Hynes, Are there dynamical effects in enzyme catalysis? Some thoughts concerning the enzymatic chemical step, Archives of Biochemistry and Biophysics, vol.582, pp.42-55, 2015.
DOI : 10.1016/j.abb.2015.06.004

A. Warshel, Dynamics of reactions in polar solvents. Semiclassical trajectory studies of electron-transfer and proton-transfer reactions, The Journal of Physical Chemistry, vol.86, issue.12, pp.2218-2224, 1982.
DOI : 10.1021/j100209a016

G. K. Schenter, B. C. Garrett, and D. G. Truhlar, The Role of Collective Solvent Coordinates and Nonequilibrium Solvation in Charge-Transfer Reactions, The Journal of Physical Chemistry B, vol.105, issue.40, pp.9672-9685, 2001.
DOI : 10.1021/jp011981k

J. Bentzien, R. P. Muller, J. Florián, and A. Warshel, Hybrid ab Initio Quantum Mechanics/Molecular Mechanics Calculations of Free Energy Surfaces for Enzymatic Reactions:?? The Nucleophilic Attack in Subtilisin, The Journal of Physical Chemistry B, vol.102, issue.12, pp.2293-2301, 1998.
DOI : 10.1021/jp973480y

Y. Zhou and Y. Zhang, Serine protease acylation proceeds with a subtle re-orientation of the histidine ring at the tetrahedral intermediate, Chem. Commun., vol.269, issue.5, pp.1577-1579, 2011.
DOI : 10.1126/science.7661987

Y. T. Chang and W. H. Miller, An empirical valence bond model for constructing global potential energy surfaces for chemical reactions of polyatomic molecular systems, The Journal of Physical Chemistry, vol.94, issue.15, pp.5884-5888, 1990.
DOI : 10.1021/j100378a052

R. P. Muller and A. Warshel, Ab Initio Calculations of Free Energy Barriers for Chemical Reactions in Solution, The Journal of Physical Chemistry, vol.99, issue.49, pp.17516-17524, 1995.
DOI : 10.1021/j100049a009

H. B. Schlegel and J. L. Sonnenberg, Empirical Valence-Bond Models for Reactive Potential Energy Surfaces Using Distributed Gaussians, Journal of Chemical Theory and Computation, vol.2, issue.4, pp.905-911, 2006.
DOI : 10.1021/ct600084p

J. L. Sonnenberg, K. F. Wong, G. A. Voth, and H. B. Schlegel, Distributed Gaussian Valence Bond Surface Derived from Ab Initio Calculations, Journal of Chemical Theory and Computation, vol.5, issue.4, pp.949-961, 2009.
DOI : 10.1021/ct800477y

G. V. Isaksen, K. H. Hopmann, J. Åqvist, and B. Brandsdal, Computer Simulations Reveal Substrate Specificity of Glycosidic Bond Cleavage in Native and Mutant Human Purine Nucleoside Phosphorylase, Biochemistry, vol.55, issue.14, pp.2153-2162, 2016.
DOI : 10.1021/acs.biochem.5b01347

M. Kazemi and J. Åqvist, Chemical reaction mechanisms in solution from brute force computational Arrhenius plots, Nature Communications, vol.22, 2015.
DOI : 10.1063/1.1740193

G. V. Isaksen, J. Åqvist, and B. Brandsdal, Thermodynamics of the Purine Nucleoside Phosphorylase Reaction Revealed by Computer Simulations, Biochemistry, vol.56, issue.1, pp.306-312, 2017.
DOI : 10.1021/acs.biochem.6b00967

N. V. Plotnikov and A. Warshel, Exploring, Refining, and Validating the Paradynamics QM/MM Sampling, The Journal of Physical Chemistry B, vol.116, issue.34, pp.10342-10356, 2012.
DOI : 10.1021/jp304678d

J. Lameira, I. Kupchencko, and A. Warshel, Enhancing Paradynamics for QM/MM Sampling of Enzymatic Reactions, The Journal of Physical Chemistry B, vol.120, issue.9, pp.2155-2164, 2016.
DOI : 10.1021/acs.jpcb.5b11966

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

C. H. Bennett, Efficient estimation of free energy differences from Monte Carlo data, Journal of Computational Physics, vol.22, issue.2, pp.245-268, 1976.
DOI : 10.1016/0021-9991(76)90078-4

A. Pohorille, C. Jarzynski, and C. Chipot, Good Practices in Free-Energy Calculations, The Journal of Physical Chemistry B, vol.114, issue.32, pp.10235-10253, 2010.
DOI : 10.1021/jp102971x

L. Shen, J. Wu, and W. Yang, Multiscale Quantum Mechanics/Molecular Mechanics Simulations with Neural Networks, Journal of Chemical Theory and Computation, vol.12, issue.10, pp.4934-4946, 2016.
DOI : 10.1021/acs.jctc.6b00663

C. J. Cramer and D. G. Truhlar, A Universal Approach to Solvation Modeling, Accounts of Chemical Research, vol.41, issue.6, pp.760-768, 2008.
DOI : 10.1021/ar800019z

J. Lameira, I. Kupchencko, and A. Warshel, Enhancing Paradynamics for QM/MM Sampling of Enzymatic Reactions, The Journal of Physical Chemistry B, vol.120, issue.9, pp.2155-64, 2016.
DOI : 10.1021/acs.jpcb.5b11966

F. Duarte, B. A. Amrein, D. Blaha-nelson, and S. C. Kamerlin, Recent advances in QM/MM free energy calculations using reference potentials, BBA) - General Subjects 2015, pp.954-965
DOI : 10.1016/j.bbagen.2014.07.008

R. A. Marcus, Chemical and Electrochemical Electron-Transfer Theory, Annual Review of Physical Chemistry, vol.15, issue.1
DOI : 10.1146/annurev.pc.15.100164.001103

K. Ando and J. Hynes, Potential Energy Surfaces and Monte Carlo Simulations, The Journal of Physical Chemistry B, vol.101, issue.49, pp.10464-10478, 1997.
DOI : 10.1021/jp970173j

C. Chipot and A. Pohorille, Free Energy Calculations: Theory and Applications in Chemistry and Biology, 2007.
DOI : 10.1007/978-3-540-38448-9

G. M. Torrie and J. P. Valleau, Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling, Journal of Computational Physics, vol.23, issue.2, pp.187-199, 1977.
DOI : 10.1016/0021-9991(77)90121-8

S. Kumar, J. M. Rosenberg, D. Bouzida, R. H. Swendsen, and P. A. Kollman, THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method, Journal of Computational Chemistry, vol.22, issue.8
DOI : 10.1887/0852743920

F. Zhu and G. Hummer, Convergence and error estimation in free energy calculations using the weighted histogram analysis method, Journal of Computational Chemistry, vol.24, issue.4, pp.453-465, 2012.
DOI : 10.1002/jcc.10313

D. K. Chakravorty, M. Kumarasiri, and A. V. Soudackov, Hammes-Schiffer, S. Implementation of Umbrella Integration Within the Framework of the Empirical Valence Bond Approach, J

C. Kronman, B. Velan, and A. Shafferman, Transition State Structure and Rate Determination for the Acylation Stage of Acetylcholinesterase Catalyzed Hydrolysis of (Acetylthio)choline, J

J. Fattebert, E. Y. Lau, B. J. Bennion, P. Huang, and F. C. Lightstone, Large-Scale First-Principles Molecular Dynamics Simulations with Electrostatic Embedding: Application to Acetylcholinesterase Catalysis, Journal of Chemical Theory and Computation, vol.11, issue.12, pp.5688-5695, 2015.
DOI : 10.1021/acs.jctc.5b00606

D. G. Truhlar, W. L. Hase, and J. Hynes, Current status of transition-state theory, The Journal of Physical Chemistry, vol.87, issue.15, pp.2664-2682, 1983.
DOI : 10.1021/j100238a003

P. Kiefer and J. Hynes, Adiabatic and nonadiabatic proton transfer rate constants in solution, Solid State Ionics, vol.168, issue.3-4, pp.219-224, 2004.
DOI : 10.1016/j.ssi.2002.12.001

N. Otte, M. Bocola, and W. Thiel, Force-field parameters for the simulation of tetrahedral intermediates of serine hydrolases, Journal of Computational Chemistry, vol.8, issue.1, pp.154-162, 2009.
DOI : 10.1016/S0166-1280(03)00285-9

L. Shen, J. Wu, and W. Yang, Multiscale Quantum Mechanics/Molecular Mechanics Simulations with Neural Networks, Journal of Chemical Theory and Computation, vol.12, issue.10, pp.4934-4946, 2016.
DOI : 10.1021/acs.jctc.6b00663