Estimating protein–ligand binding free energy: Atomic solvation parameters for partition coefficient and solvation free energy calculation

Solvation energy calculation is one of the main difficulties for the estimation of protein–ligand binding free energy and the correct scoring in docking studies. We have developed a new solvation energy estimation method for protein–ligand binding based on atomic solvation parameter (ASP), which has been shown to improve the power of protein–ligand binding free energy predictions. The ASP set, designed to handle both proteins and organic compounds and derived from experimental n‐octanol/water partition coefficient (log P) data, contains 100 atom types (united model that treats hydrogen atoms implicitly) or 119 atom types (all‐atom model that treats hydrogen atoms explicitly). By using this unified ASP set, an algorithm was developed for solvation energy calculation and was further integrated into a score function for predicting protein–ligand binding affinity. The score function reproduced the absolute binding free energies of a test set of 50 protein–ligand complexes with a standard error of 8.31 kJ/mol. As a byproduct, a conformation‐dependent log P calculation algorithm named ASPLOGP was also implemented. The predictive results of ASPLOGP for a test set of 138 compounds were r = 0.968, s = 0.344 for the all‐atom model and r = 0.962, s = 0.367 for the united model, which were better than previous conformation‐dependent approaches and comparable to fragmental and atom‐based methods. ASPLOGP also gave good predictive results for small peptides. The score function based on the ASP model can be applied widely in protein–ligand interaction studies and structure‐based drug design. Proteins 2004. © 2004 Wiley‐Liss, Inc.

[1]  W. C. Still,et al.  Semianalytical treatment of solvation for molecular mechanics and dynamics , 1990 .

[2]  John B. O. Mitchell,et al.  Protein Ligand Database (PLD): additional understanding of the nature and specificity of protein-ligand complexes , 2003, Bioinform..

[3]  A. D. McLachlan,et al.  Solvation energy in protein folding and binding , 1986, Nature.

[4]  Glen Eugene Kellogg,et al.  HINT: A new method of empirical hydrophobic field calculation for CoMFA , 1991, J. Comput. Aided Mol. Des..

[5]  Tingjun Hou,et al.  ADME evaluation in drug discovery , 2002, Journal of molecular modeling.

[6]  G. V. Paolini,et al.  Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes , 1997, J. Comput. Aided Mol. Des..

[7]  A. H. Juffer,et al.  Comparison of atomic solvation parametric sets: Applicability and limitations in protein folding and binding , 1995, Protein science : a publication of the Protein Society.

[8]  W. C. Still,et al.  The GB/SA Continuum Model for Solvation. A Fast Analytical Method for the Calculation of Approximate Born Radii , 1997 .

[9]  Xiaojie Xu,et al.  Empirical Aqueous Solvation Models Based on Accessible Surface Areas with Implicit Electrostatics , 2002 .

[10]  L. Lai,et al.  Calculating partition coefficient by atom-additive method , 2000 .

[11]  Hans-Joachim Böhm,et al.  The computer program LUDI: A new method for the de novo design of enzyme inhibitors , 1992, J. Comput. Aided Mol. Des..

[12]  D. Eisenberg,et al.  Atomic solvation parameters applied to molecular dynamics of proteins in solution , 1992, Protein science : a publication of the Protein Society.

[13]  Luhua Lai,et al.  A New Atom-Additive Method for Calculating Partition Coefficients , 1997, J. Chem. Inf. Comput. Sci..

[14]  Luhua Lai,et al.  SCORE: A New Empirical Method for Estimating the Binding Affinity of a Protein-Ligand Complex , 1998 .

[15]  Salvatore Cannistraro,et al.  Molecular Dynamics of Water at the Protein-Solvent Interface , 2002 .

[16]  H. Meirovitch,et al.  On the transferability of atomic solvation parameters: Ab initio structural prediction of cyclic heptapeptides in DMSO. , 2000, Biopolymers.

[17]  R. Cramer,et al.  Validation of the general purpose tripos 5.2 force field , 1989 .

[18]  Richard A. Friesner,et al.  An automatic three-dimensional finite element mesh generation system for the Poisson-Boltzmann equation , 1997, J. Comput. Chem..

[19]  Renxiao Wang,et al.  Comparative evaluation of 11 scoring functions for molecular docking. , 2003, Journal of medicinal chemistry.

[20]  Luhua Lai,et al.  Calculating Partition Coefficients of Peptides by the Addition Method , 1999 .

[21]  Tingjun Hou,et al.  ADME Evaluation in Drug Discovery. 2. Prediction of Partition Coefficient by Atom-Additive Approach Based on Atom-Weighted Solvent Accessible Surface Areas , 2003, J. Chem. Inf. Comput. Sci..

[22]  Glen E. Kellogg,et al.  Hydrophobicity: is LogPo/w more than the sum of its parts? , 2000 .

[23]  P. Kollman,et al.  Solvation Model Based on Weighted Solvent Accessible Surface Area , 2001 .

[24]  Hongyi Zhou,et al.  Stability scale and atomic solvation parameters extracted from 1023 mutation experiments , 2002, Proteins.

[25]  W. Meylan,et al.  Atom/fragment contribution method for estimating octanol-water partition coefficients. , 1995, Journal of pharmaceutical sciences.

[26]  B Testa,et al.  Esters of L‐Dopa: Structure‐hydrolysis Relationships and Ability to Induce Circling Behaviour in an Experimental Model of Hemiparkinsonism , 1995, The Journal of pharmacy and pharmacology.

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

[28]  Werner Braun,et al.  Exact and efficient analytical calculation of the accessible surface areas and their gradients for macromolecules , 1998, J. Comput. Chem..

[29]  H. Scheraga,et al.  Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Mannhold,et al.  Calculation Procedures for Molecular Lipophilicity: a Comparative Study† , 1996 .

[31]  Hans-Joachim Böhm,et al.  The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure , 1994, J. Comput. Aided Mol. Des..

[32]  Luhua Lai,et al.  Further development and validation of empirical scoring functions for structure-based binding affinity prediction , 2002, J. Comput. Aided Mol. Des..