Ab Initio prediction of protein–ligand binding structures by replica‐exchange umbrella sampling simulations

We have developed a prediction method for the binding structures of ligands with proteins. Our method consists of three steps. First, replica‐exchange umbrella sampling simulations are performed along the distance between a putative binding site of a protein and a ligand as the reaction coordinate. Second, we obtain the potential of mean force (PMF) of the unbiased system using the weighted histogram analysis method and determine the distance that corresponds to the global minimum of PMF. Third, structures that have this global‐minimum distance and energy values around the average potential energy are collected and analyzed using the principal component analysis. We predict the binding structure as the global‐minimum free energy state on the free energy landscapes along the two major principal component axes. As test cases, we applied our method to five protein–ligand complex systems. Starting from the configuration in which the protein and the ligand are far away from each other in each system, our method predicted the ligand binding structures in excellent agreement with the experimental data from Protein Data Bank. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011

[1]  C. Anfinsen Principles that govern the folding of protein chains. , 1973, Science.

[2]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[3]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[4]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[5]  David A. Case,et al.  Harmonic and quasiharmonic descriptions of crambin , 1990 .

[6]  Fumio Hirata,et al.  The effects of solvent on the conformation and the collective motions of protein: normal mode analysis and molecular dynamics simulations of melittin in water and in vacuum , 1991 .

[7]  García,et al.  Large-amplitude nonlinear motions in proteins. , 1992, Physical review letters.

[8]  R. Swendsen,et al.  THE weighted histogram analysis method for free‐energy calculations on biomolecules. I. The method , 1992 .

[9]  P Argos,et al.  Optimal protocol and trajectory visualization for conformational searches of peptides and proteins. , 1992, Journal of molecular biology.

[10]  P. Kollman,et al.  A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char , 1993 .

[11]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[12]  H. Berendsen,et al.  Essential dynamics of proteins , 1993, Proteins.

[13]  Peter A. Kollman,et al.  FREE ENERGY CALCULATIONS : APPLICATIONS TO CHEMICAL AND BIOCHEMICAL PHENOMENA , 1993 .

[14]  Peter A. Kollman,et al.  Application of the multimolecule and multiconformational RESP methodology to biopolymers: Charge derivation for DNA, RNA, and proteins , 1995, J. Comput. Chem..

[15]  P Willett,et al.  Development and validation of a genetic algorithm for flexible docking. , 1997, Journal of molecular biology.

[16]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[17]  N. Go,et al.  Investigating protein dynamics in collective coordinate space. , 1999, Current opinion in structural biology.

[18]  Thomas Lengauer,et al.  Evaluation of the FLEXX incremental construction algorithm for protein–ligand docking , 1999, Proteins.

[19]  Y. Sugita,et al.  Multidimensional replica-exchange method for free-energy calculations , 2000, cond-mat/0009120.

[20]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[21]  P. Kollman,et al.  Binding of a diverse set of ligands to avidin and streptavidin: an accurate quantitative prediction of their relative affinities by a combination of molecular mechanics and continuum solvent models. , 2000, Journal of medicinal chemistry.

[22]  A Mitsutake,et al.  Generalized-ensemble algorithms for molecular simulations of biopolymers. , 2000, Biopolymers.

[23]  Benoît Roux,et al.  Extension to the weighted histogram analysis method: combining umbrella sampling with free energy calculations , 2001 .

[24]  A. Roitberg,et al.  All-atom structure prediction and folding simulations of a stable protein. , 2002, Journal of the American Chemical Society.

[25]  Michael R. Shirts,et al.  Simulation of folding of a small alpha-helical protein in atomistic detail using worldwide-distributed computing. , 2002, Journal of molecular biology.

[26]  William Swope,et al.  Understanding folding and design: Replica-exchange simulations of ``Trp-cage'' miniproteins , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  S. Weerasinghe,et al.  A Kirkwood−Buff Derived Force Field for Mixtures of Urea and Water , 2003 .

[28]  Yoshitake Sakae,et al.  Optimization of protein force-field parameters with the Protein Data Bank , 2003, cond-mat/0309110.

[29]  Samantha Weerasinghe,et al.  Kirkwood–Buff derived force field for mixtures of acetone and water , 2003 .

[30]  S. Weerasinghe,et al.  A Kirkwood–Buff derived force field for sodium chloride in water , 2003 .

[31]  Y. Okamoto,et al.  Prediction of membrane protein structures by replica-exchange Monte Carlo simulations: case of two helices. , 2004, The Journal of chemical physics.

[32]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[33]  Yuko Okamoto,et al.  Prediction of transmembrane helix configurations by replica-exchange simulations , 2003, cond-mat/0309338.

[34]  Y. Okamoto,et al.  Self-assembly of transmembrane helices of bacteriorhodopsin by a replica-exchange Monte Carlo simulation , 2004 .

[35]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[36]  S. Weerasinghe,et al.  A Kirkwood-Buff derived force field for methanol and aqueous methanol solutions. , 2005, The journal of physical chemistry. B.

[37]  Y. Sakae,et al.  Secondary-Structure Design of Proteins by a Backbone Torsion Energy(Cross-disciplinary Physics and Related Areas of Science and Technology) , 2005, cond-mat/0512564.

[38]  Gerald M. Maggiora,et al.  On Outliers and Activity Cliffs-Why QSAR Often Disappoints , 2006, J. Chem. Inf. Model..

[39]  P. Kollman,et al.  Automatic atom type and bond type perception in molecular mechanical calculations. , 2006, Journal of molecular graphics & modelling.

[40]  Matthew P. Repasky,et al.  Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. , 2006, Journal of medicinal chemistry.

[41]  V. Hornak,et al.  Comparison of multiple Amber force fields and development of improved protein backbone parameters , 2006, Proteins.

[42]  B Montgomery Pettitt,et al.  Preferential solvation in urea solutions at different concentrations: properties from simulation studies. , 2007, The journal of physical chemistry. B.

[43]  B Montgomery Pettitt,et al.  Molecular basis of the apparent near ideality of urea solutions. , 2007, Biophysical journal.

[44]  Hongxing Lei,et al.  Ab initio folding of albumin binding domain from all-atom molecular dynamics simulation. , 2007, The journal of physical chemistry. B.

[45]  K. Dill,et al.  The protein folding problem. , 1993, Annual review of biophysics.

[46]  Stephen R. Johnson,et al.  The Trouble with QSAR (or How I Learned To Stop Worrying and Embrace Fallacy) , 2008, J. Chem. Inf. Model..

[47]  Yuko Okamoto,et al.  Analysis of helix-helix interactions of bacteriorhodopsin by replica-exchange simulations. , 2009, Biophysical journal.

[48]  Gillian C. Lynch,et al.  Backbone additivity in the transfer model of protein solvation , 2010, Protein science : a publication of the Protein Society.

[49]  Jacob D. Durrant,et al.  Computer-aided drug-discovery techniques that account for receptor flexibility. , 2010, Current opinion in pharmacology.

[50]  Yuko Okamoto,et al.  Dependency of ligand free energy landscapes on charge parameters and solvent models , 2010, J. Comput. Aided Mol. Des..

[51]  Yuko Okamoto,et al.  Hydrophobic core formation and dehydration in protein folding studied by generalized-ensemble simulations. , 2010, Biophysical journal.

[52]  J Andrew McCammon,et al.  Large conformational changes in proteins: signaling and other functions. , 2010, Current opinion in structural biology.

[53]  Yuko Okamoto,et al.  Replica-exchange method in van der Waals radius space: overcoming steric restrictions for biomolecules. , 2009, The Journal of chemical physics.

[54]  Joseph A. Bank,et al.  Supporting Online Material Materials and Methods Figs. S1 to S10 Table S1 References Movies S1 to S3 Atomic-level Characterization of the Structural Dynamics of Proteins , 2022 .