Abstract

It is of great interest in modern drug design to accurately calculate the free energies of protein-ligand or nucleic acid-ligand binding. MM-PBSA (Molecular Mechanics-Poisson Boltzmann Surface Area) and MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) have gained popularity in this field. For both methods, the conformational entropy, which is usually calculated through normal mode analysis (NMA), is needed to calculate the absolute binding free energies. Unfortunately, NMA is computationally demanding and becomes a bottleneck of the MM-PB/GBSA-NMA methods. In this work, we have developed a fast approach to estimate the conformational entropy based upon solvent accessible surface area calculations. In our approach, the conformational entropy of a molecule, S, can be obtained by summing up the contributions of all atoms, no matter they are buried or exposed. Each atom has two types of surface areas, solvent accessible surface area (SAS) and buried SAS (BSAS). The two types of surface areas are weighted to estimate the contribution of an atom to S. Atoms having the same atom type share the same weight and a general parameter k is applied to balance the contributions of the two types of surface areas.

Keywords

In silico; Anticancer Peptide; SVS-1; multipharmacophore; drug-like; efficator; Preceding; Membrane Neutralization; multi-mimotopic; algorithmic approach; biclustering analysis; expression data; Develop and Test; Solvent Accessible; Surface Area-Based Model; Conformational Entropy; Calculations; Conformational Entropy, Configurational Entropy, WSAS, Solvent Accessible Surface Area, MM-PBSA, MM-GBSA, Binding Free Energy Calculations, Protein Design, Drug Design.