New Parameters for Higher Accuracy in the Computation of Binding Free Energy Differences upon Alanine Scanning Mutagenesis on Protein-Protein Interfaces

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Simoes, ICM (Author) Other; Costa, IPD (Author) Other; Coimbra, JTS (Author) Other; Ramos, MJ (Author) FCUP; Pedro A Fernandes (Author) FCUP

Journal

Title: Journal of Chemical Information and Modeling

Vol. 57

Pages: 60-72

ISSN: 1549-9596

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 38 Citations

Scopus - 40 Citations

Other information

Authenticus ID: P-00M-F0Y

DOI: 10.1021/acs.jcim.6b00378

Abstract (EN): Knowing how proteins make stable complexes enables the development of inhibitors to preclude protein MM-PBSA protein (P:P) binding. The identification of the specific interfacial residues that mostly contribute to protein binding, denominated as hot spots, is thus critical. Here, we refine an in silico alanine scanning mutagenesis protocol, based on a residue-dependent dielectric constant version of the Molecular Mechanics/Poisson-Boltzmann Surface Area method. We have used a large data set of structurally diverse P:P complexes to redefine the residue-dependent dielectric constants used in the determination of binding free energies. The accuracy of the method was validated through comparison with experimental data, considering the per-residue P:P binding free energy (Delta Delta G(bmding)) differences upon alanine mutation. Different protocols were tested, i.e., a geometry optimization protocol and three molecular dynamics (MD) protocols: (1) one using explicit water molecules, (2) another with an implicit solvation model, and (3) a third where we have carried out an accelerated MD with explicit water molecules. Using a set of protein dielectric constants (within the range from 1 to 20) we showed that the dielectric constants of 7 for nonpolar and polar. residues and 11 for charged residues (and histidine) provide optimal Delta Delta G(binding) predictions. An overall mean unsigned error (MUE) of 1.4 kcal mol(-1) relative to the experiment was achieved in 210 mutations only with geometry optimization, which was further reduced with MD simulations (MUE of 1.1 kcal mol(-1) for the MD employing explicit solvent). This recalibrated method allows for a better computational identification of hot spots, avoiding expensive and time-consuming experiments or thermodynamic integration/ free energy perturbation/ uBAR calculations, and will hopefully help new drug discovery campaigns in their quest of searching spots of interest for binding small drug-like molecules at P:P interfaces.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13