Exact reaction coordinates for flap opening in HIV-1 protease

Wu, Shanshan; Li, Huiyu; Ma, Ao

doi:10.1073/pnas.2214906119

Exact reaction coordinates for flap opening in HIV-1 protease

Journal Article · Thu Dec 01 23:00:00 EST 2022 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2214906119· OSTI ID:2423229

Wu, Shanshan ^[1]; ^[1]; ^[1]

Center for Bioinformatics and Quantitative Biology, Richard and Loan Hill Department of Biomedical Engineering, The University of Illinois at Chicago, Chicago, IL 60607

The primary goal of protein science is to understand how proteins function, which requires understanding the functional dynamics responsible for transitions between different functional structures of a protein. A central concept is the exact reaction coordinates that can determine the value of committor for any protein configuration, which provide the optimal description of functional dynamics. Despite intensive efforts, identifying the exact reaction coordinates (RCs) in complex molecules remains a formidable challenge. Using the recently developed generalized work functional, we report the discovery of the exact RCs for an important functional process—the flap opening of HIV-1 protease. Our results show that this process has six RCs, each one is a linear combination of ~240 backbone dihedrals, providing the precise definition of collectivity and cooperativity in the functional dynamics of a protein. Applying bias potentials along each RC can accelerate flap opening by $10^{3}$ to $10^{4}$ folds. The success in identifying the RCs of a protein with 198 residues represents a significant progress beyond that of the alanine dipeptide, currently the only other complex molecule for which the exact RCs for its conformational changes are known. Our results suggest that the generalized work functional (GWF) might be the fundamental operator of mechanics that controls protein dynamics.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Argonne Leadership Computing Facility (ALCF)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423229

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 49 Vol. 119; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

References (66)

Quasi-harmonic method for studying very low frequency modes in proteins Levy, R. M.; Srinivasan, A. R.; Olson, W. K. Biopolymers, Vol. 23, Issue 6 https://doi.org/10.1002/bip.360230610	journal	June 1984
Exploring protein native states and large-scale conformational changes with a modified generalized born model Onufriev, Alexey; Bashford, Donald; Case, David A. Proteins: Structure, Function, and Bioinformatics, Vol. 55, Issue 2 https://doi.org/10.1002/prot.20033	journal	March 2004
Improved side-chain torsion potentials for the Amber ff99SB protein force field Lindorff-Larsen, Kresten; Piana, Stefano; Palmo, Kim Proteins: Structure, Function, and Bioinformatics https://doi.org/10.1002/prot.22711	journal	January 2010
Funnels, pathways, and the energy landscape of protein folding: A synthesis Bryngelson, Joseph D.; Onuchic, José Nelson; Socci, Nicholas D. Proteins: Structure, Function, and Genetics, Vol. 21, Issue 3 https://doi.org/10.1002/prot.340210302	journal	March 1995
Statistical theory of the decay of metastable states Langer, J. S. Annals of Physics, Vol. 54, Issue 2 https://doi.org/10.1016/0003-4916(69)90153-5	journal	September 1969
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C. Journal of Computational Physics, Vol. 23, Issue 3 https://doi.org/10.1016/0021-9991(77)90098-5	journal	March 1977
Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling Torrie, G. M.; Valleau, J. P. Journal of Computational Physics, Vol. 23, Issue 2 https://doi.org/10.1016/0021-9991(77)90121-8	journal	February 1977
The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU Spinelli, S.; Liu, Q.; Alzari, P. Biochimie, Vol. 73, Issue 11 https://doi.org/10.1016/0300-9084(91)90169-2	journal	November 1991
On the eigenfunctions of the Fokker-Planck operator and of its adjoint Ryter, D. Physica A: Statistical Mechanics and its Applications, Vol. 142, Issue 1-3 https://doi.org/10.1016/0378-4371(87)90019-7	journal	April 1987
“Wide-Open” 1.3 Å Structure of a Multidrug-Resistant HIV-1 Protease as a Drug Target Martin, Philip; Vickrey, John F.; Proteasa, Gheorghe Structure, Vol. 13, Issue 12 https://doi.org/10.1016/j.str.2005.11.005	journal	December 2005
Ligand Binding Pathways and Conformational Transitions of the HIV Protease Miao, Yinglong; Huang, Yu-ming M.; Walker, Ross C. Biochemistry, Vol. 57, Issue 9 https://doi.org/10.1021/acs.biochem.7b01248	journal	February 2018
Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond Matthew, Ashley N.; Leidner, Florian; Lockbaum, Gordon J. Chemical Reviews, Vol. 121, Issue 6 https://doi.org/10.1021/acs.chemrev.0c00648	journal	January 2021
Chasing Collective Variables Using Autoencoders and Biased Trajectories Belkacemi, Zineb; Gkeka, Paraskevi; Lelièvre, Tony Journal of Chemical Theory and Computation, Vol. 18, Issue 1 https://doi.org/10.1021/acs.jctc.1c00415	journal	December 2021
A Rigorous Method for Identifying a One-Dimensional Reaction Coordinate in Complex Molecules Wu, Shanshan; Li, Huiyu; Ma, Ao Journal of Chemical Theory and Computation, Vol. 18, Issue 5 https://doi.org/10.1021/acs.jctc.2c00132	journal	April 2022
Exact Topology of the Dynamic Probability Surface of an Activated Process by Persistent Homology Manuchehrfar, Farid; Li, Huiyu; Tian, Wei The Journal of Physical Chemistry B, Vol. 125, Issue 18 https://doi.org/10.1021/acs.jpcb.1c00904	journal	May 2021
Data-Driven Collective Variables for Enhanced Sampling Bonati, Luigi; Rizzi, Valerio; Parrinello, Michele The Journal of Physical Chemistry Letters, Vol. 11, Issue 8 https://doi.org/10.1021/acs.jpclett.0c00535	journal	April 2020
Variational transition-state theory Truhlar, Donald G.; Garrett, Bruce C. Accounts of Chemical Research, Vol. 13, Issue 12 https://doi.org/10.1021/ar50156a002	journal	December 1980
GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation Hess, Berk; Kutzner, Carsten; van der Spoel, David Journal of Chemical Theory and Computation, Vol. 4, Issue 3 https://doi.org/10.1021/ct700301q	journal	February 2008
Classical and modern methods in reaction rate theory Berne, Bruce J.; Borkovec, Michal; Straub, John E. The Journal of Physical Chemistry, Vol. 92, Issue 13 https://doi.org/10.1021/j100324a007	journal	June 1988
Fast Peptidyl cis−trans Isomerization within the Flexible Gly-Rich Flaps of HIV-1 Protease Hamelberg, Donald; McCammon, J. Andrew Journal of the American Chemical Society, Vol. 127, Issue 40 https://doi.org/10.1021/ja054338a	journal	September 2005
Unbiased Molecular Dynamics of 11 min Timescale Drug Unbinding Reveals Transition State Stabilizing Interactions Lotz, Samuel D.; Dickson, Alex Journal of the American Chemical Society, Vol. 140, Issue 2 https://doi.org/10.1021/jacs.7b08572	journal	January 2018
Markov State Models: From an Art to a Science Husic, Brooke E.; Pande, Vijay S. Journal of the American Chemical Society, Vol. 140, Issue 7 https://doi.org/10.1021/jacs.7b12191	journal	February 2018
Grid−Flux Method for Learning the Solvent Contribution to the Mechanisms of Reactions McCormick, Thomas A.; Chandler, David The Journal of Physical Chemistry B, Vol. 107, Issue 12 https://doi.org/10.1021/jp027290l	journal	February 2003
Automatic Method for Identifying Reaction Coordinates in Complex Systems ^† Ma, Ao; Dinner, Aaron R. The Journal of Physical Chemistry B, Vol. 109, Issue 14 https://doi.org/10.1021/jp045546c	journal	April 2005
Revisiting and Computing Reaction Coordinates with Directional Milestoning Kirmizialtin, Serdal; Elber, Ron The Journal of Physical Chemistry A, Vol. 115, Issue 23 https://doi.org/10.1021/jp111093c	journal	April 2011
The Adaptive Biasing Force Method: Everything You Always Wanted To Know but Were Afraid To Ask Comer, Jeffrey; Gumbart, James C.; Hénin, Jérôme The Journal of Physical Chemistry B, Vol. 119, Issue 3 https://doi.org/10.1021/jp506633n	journal	August 2014
Dynamic personalities of proteins Henzler-Wildman, Katherine; Kern, Dorothee Nature, Vol. 450, Issue 7172 https://doi.org/10.1038/nature06522	journal	December 2007
From Levinthal to pathways to funnels Dill, Ken A.; Chan, Hue Sun Nature Structural & Molecular Biology, Vol. 4, Issue 1 https://doi.org/10.1038/nsb0197-10	journal	January 1997
VAMPnets for deep learning of molecular kinetics Mardt, Andreas; Pasquali, Luca; Wu, Hao Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-017-02388-1	journal	January 2018
Past–future information bottleneck for sampling molecular reaction coordinate simultaneously with thermodynamics and kinetics Wang, Yihang; Ribeiro, João Marcelo Lamim; Tiwary, Pratyush Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-11405-4	journal	August 2019
The transition state method Wigner, E. Transactions of the Faraday Society, Vol. 34 https://doi.org/10.1039/tf9383400029	journal	January 1938
Calculating free energies using average force Darve, Eric; Pohorille, Andrew The Journal of Chemical Physics, Vol. 115, Issue 20 https://doi.org/10.1063/1.1410978	journal	November 2001
A temperature-dependent nudged-elastic-band algorithm Crehuet, Ramon; Field, Martin J. The Journal of Chemical Physics, Vol. 118, Issue 21 https://doi.org/10.1063/1.1571817	journal	June 2003
One-dimensional reaction coordinates for diffusive activated rate processes in many dimensions Berezhkovskii, Alexander; Szabo, Attila The Journal of Chemical Physics, Vol. 122, Issue 1 https://doi.org/10.1063/1.1818091	journal	December 2004
Obtaining reaction coordinates by likelihood maximization Peters, Baron; Trout, Bernhardt L. The Journal of Chemical Physics, Vol. 125, Issue 5 https://doi.org/10.1063/1.2234477	journal	August 2006
Dihedral angle principal component analysis of molecular dynamics simulations Altis, Alexandros; Nguyen, Phuong H.; Hegger, Rainer The Journal of Chemical Physics, Vol. 126, Issue 24 https://doi.org/10.1063/1.2746330	journal	June 2007
The stochastic separatrix and the reaction coordinate for complex systems Antoniou, Dimitri; Schwartz, Steven D. The Journal of Chemical Physics, Vol. 130, Issue 15 https://doi.org/10.1063/1.3123162	journal	April 2009
Simultaneous escaping of explicit and hidden free energy barriers: Application of the orthogonal space random walk strategy in generalized ensemble based conformational sampling Zheng, Lianqing; Chen, Mengen; Yang, Wei The Journal of Chemical Physics, Vol. 130, Issue 23 https://doi.org/10.1063/1.3153841	journal	June 2009
Statistical mechanics of isomerization dynamics in liquids and the transition state approximation Chandler, David The Journal of Chemical Physics, Vol. 68, Issue 6 https://doi.org/10.1063/1.436049	journal	January 1978
The stable states picture of chemical reactions. II. Rate constants for condensed and gas phase reaction models Grote, Richard F.; Hynes, James T. The Journal of Chemical Physics, Vol. 73, Issue 6 https://doi.org/10.1063/1.440485	journal	September 1980
Diffusion-controlled reactions: A variational formula for the optimum reaction coordinate Berkowitz, Max; Morgan, J. D.; McCammon, J. A. The Journal of Chemical Physics, Vol. 79, Issue 11 https://doi.org/10.1063/1.445675	journal	December 1983
The MaxFlux algorithm for calculating variationally optimized reaction paths for conformational transitions in many body systems at finite temperature Huo, Shuanghong; Straub, John E. The Journal of Chemical Physics, Vol. 107, Issue 13 https://doi.org/10.1063/1.474863	journal	October 1997
On the transition coordinate for protein folding Du, Rose; Pande, Vijay S.; Grosberg, Alexander Yu. The Journal of Chemical Physics, Vol. 108, Issue 1 https://doi.org/10.1063/1.475393	journal	January 1998
Reaction mechanism and reaction coordinates from the viewpoint of energy flow Li, Wenjin; Ma, Ao The Journal of Chemical Physics, Vol. 144, Issue 11 https://doi.org/10.1063/1.4943581	journal	March 2016
Kinetic energy flows in activated dynamics of biomolecules Li, Huiyu; Ma, Ao The Journal of Chemical Physics, Vol. 153, Issue 9 https://doi.org/10.1063/5.0020275	journal	September 2020
An extended autoencoder model for reaction coordinate discovery in rare event molecular dynamics datasets Frassek, M.; Arjun, A.; Bolhuis, P. G. The Journal of Chemical Physics, Vol. 155, Issue 6 https://doi.org/10.1063/5.0058639	journal	August 2021
Phase space geometry of isolated to condensed chemical reactions Nagahata, Yutaka; Hernandez, Rigoberto; Komatsuzaki, Tamiki The Journal of Chemical Physics, Vol. 155, Issue 21 https://doi.org/10.1063/5.0059618	journal	December 2021
Explaining reaction coordinates of alanine dipeptide isomerization obtained from deep neural networks using Explainable Artificial Intelligence (XAI) Kikutsuji, Takuma; Mori, Yusuke; Okazaki, Kei-ichi The Journal of Chemical Physics, Vol. 156, Issue 15 https://doi.org/10.1063/5.0087310	journal	April 2022
HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations Hornak, V.; Okur, A.; Rizzo, R. C. Proceedings of the National Academy of Sciences, Vol. 103, Issue 4 https://doi.org/10.1073/pnas.0508452103	journal	January 2006
Reaction coordinate of an enzymatic reaction revealed by transition path sampling Quaytman, S. L.; Schwartz, S. D. Proceedings of the National Academy of Sciences, Vol. 104, Issue 30 https://doi.org/10.1073/pnas.0704304104	journal	July 2007
Random walk in orthogonal space to achieve efficient free-energy simulation of complex systems Zheng, L.; Chen, M.; Yang, W. Proceedings of the National Academy of Sciences, Vol. 105, Issue 51 https://doi.org/10.1073/pnas.0810631106	journal	December 2008
Reaction coordinates of biomolecular isomerization Bolhuis, P. G.; Dellago, C.; Chandler, D. Proceedings of the National Academy of Sciences, Vol. 97, Issue 11 https://doi.org/10.1073/pnas.100127697	journal	May 2000
Native contacts determine protein folding mechanisms in atomistic simulations Best, R. B.; Hummer, G.; Eaton, W. A. Proceedings of the National Academy of Sciences, Vol. 110, Issue 44 https://doi.org/10.1073/pnas.1311599110	journal	October 2013
Spectral gap optimization of order parameters for sampling complex molecular systems Tiwary, Pratyush; Berne, B. J. Proceedings of the National Academy of Sciences, Vol. 113, Issue 11 https://doi.org/10.1073/pnas.1600917113	journal	February 2016
Escaping free-energy minima Laio, A.; Parrinello, M. Proceedings of the National Academy of Sciences, Vol. 99, Issue 20 https://doi.org/10.1073/pnas.202427399	journal	September 2002
Deep learning the slow modes for rare events sampling Bonati, Luigi; Piccini, GiovanniMaria; Parrinello, Michele Proceedings of the National Academy of Sciences, Vol. 118, Issue 44 https://doi.org/10.1073/pnas.2113533118	journal	October 2021
Recent developments in methods for identifying reaction coordinates Li, Wenjin; Ma, Ao Molecular Simulation, Vol. 40, Issue 10-11 https://doi.org/10.1080/08927022.2014.907898	journal	April 2014
The geometry of reaction dynamics Uzer, T.; Jaffé, Charles; Palacián, Jesús Nonlinearity, Vol. 15, Issue 4 https://doi.org/10.1088/0951-7715/15/4/301	journal	April 2002
Initial Recombination of Ions Onsager, L. Physical Review, Vol. 54, Issue 8 https://doi.org/10.1103/PhysRev.54.554	journal	October 1938
Well-Tempered Metadynamics: A Smoothly Converging and Tunable Free-Energy Method Barducci, Alessandro; Bussi, Giovanni; Parrinello, Michele Physical Review Letters, Vol. 100, Issue 2 https://doi.org/10.1103/PhysRevLett.100.020603	journal	January 2008
Reaction-rate theory: fifty years after Kramers Hänggi, Peter; Talkner, Peter; Borkovec, Michal Reviews of Modern Physics, Vol. 62, Issue 2 https://doi.org/10.1103/RevModPhys.62.251	journal	April 1990
Entropic barriers, transition states, funnels, and exponential protein folding kinetics: A simple model Bicout, D. J.; Szabo, Attila Protein Science, Vol. 9, Issue 3 https://doi.org/10.1110/ps.9.3.452	journal	January 2000
How Fast-Folding Proteins Fold Lindorff-Larsen, K.; Piana, S.; Dror, R. O. Science, Vol. 334, Issue 6055 https://doi.org/10.1126/science.1208351	journal	October 2011
The energy landscapes and motions of proteins Frauenfelder, H.; Sligar, S.; Wolynes, P. Science, Vol. 254, Issue 5038 https://doi.org/10.1126/science.1749933	journal	December 1991
Boltzmann generators: Sampling equilibrium states of many-body systems with deep learning Noé, Frank; Olsson, Simon; Köhler, Jonas Science, Vol. 365, Issue 6457 https://doi.org/10.1126/science.aaw1147	journal	September 2019
T RANSITION P ATH S AMPLING : Throwing Ropes Over Rough Mountain Passes, in the Dark Bolhuis, Peter G.; Chandler, David; Dellago, Christoph Annual Review of Physical Chemistry, Vol. 53, Issue 1 https://doi.org/10.1146/annurev.physchem.53.082301.113146	journal	October 2002

Similar Records

Mid-infrared trace detection with parts-per-quadrillion quantitation accuracy: Expanding frontiers of radiocarbon sensing

Journal Article · Thu Mar 21 00:00:00 EDT 2024 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:2326247

Designing multicomponent hydrides with potential high T _c superconductivity

Journal Article · Mon Nov 04 23:00:00 EST 2024 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:2475896

Ground-state phase diagram of the t-t ′ -J model

Journal Article · Wed Oct 27 00:00:00 EDT 2021 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1828997

Related Subjects

Science & Technology - Other Topics

Exact reaction coordinates for flap opening in HIV-1 protease

Citation Formats

References (66)

Similar Records

Related Subjects