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.
Pei
Jianfeng
J
State Key Laboratory for Structural Chemistry of Stable and Unstable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
Wang
Qi
Q
Zhou
Jiaju
J
Lai
Luhua
L
D030562:Databases, Protein; D008024:Ligands; D046911:Macromolecular Substances; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000737:chemistry; D012984:Software; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics
D008024:Ligands; D046911:Macromolecular Substances; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides; D011506:Proteins; D018040:Receptors, Neurokinin-1; D012997:Solvents