Interaction Entropy for Computational Alanine Scanning

Abstract

The theoretical calculation of protein-protein binding free energy is a grand challenge in computational biology. Accurate prediction of critical residues along with their specific and quantitative contributions to protein-protein binding free energy is extremely helpful to reveal binding mechanisms and identify drug-like molecules that alter protein-protein interactions. In this paper, we propose an interaction entropy approach combined with the molecular mechanics/generalized Born surface area (MM/GBSA) method for solvation to compute residue-specific protein-protein binding free energy. In the current approach, the entropic loss in binding free energy of individual residues is explicitly computed from moledular dynamics (MD) simulation by using the interaction entropy method. In this approach the entropic contribution to binding free energy is determined from fluctuation of the interaction in MD simulation. Studies for an extensive set of realistic protein-protein interaction systems showed that by including the entropic contribution, the computed residue-specific binding free energies are in better agreement with the corresponding experimental data.

Binding Modes of Small‐Molecule Inhibitors to the EED Pocket of PRC2

“…[51,55,56] Since we will adopt the singletrajectory approach that doesn't consider the conformational change after mutation, we assume that the gas-phase binding free energy difference between the mutant protein-ligand interaction (P a -L) and the wild type protein-ligand interaction (P x -L) is equivalent to that between residue a-ligand interaction (a-L) and residue x-ligand interaction (x-L). [51,55,56] Since we will adopt the singletrajectory approach that doesn't consider the conformational change after mutation, we assume that the gas-phase binding free energy difference between the mutant protein-ligand interaction (P a -L) and the wild type protein-ligand interaction (P x -L) is equivalent to that between residue a-ligand interaction (a-L) and residue x-ligand interaction (x-L).…”

“…The change in binding free energy upon alanine mutation ( DDG c!a bind ) is defined as [51][52][53][54][55][56][57] …”

Exploring the Reasons for Decrease in Binding Affinity of HIV-2 Against HIV-1 Protease Complex Using Interaction Entropy Under Polarized Force Field

“…In the IE method, the residue decomposition of entropy change (Wang et al, 2017; Yan et al, 2017) is performed by the following equations:…”

“…The method considers the internal motions of protein as superposition of vibrations with different frequencies (Xu et al, 2011), and then calculates the vibrational entropy. Besides, the calculation of Hessian matrix of the energy (second derivative of energy) is extremely costly in multiple degrees of freedom (Yan et al, 2017). Ray Luo, the developer of MM/PBSA, finds that the normal mode approximation does not benefit too much to the quality of the MM/PBSA calculations (Wang et al, 2016).…”

“…In this paper, a novel and effective method, namely interaction entropy (IE) (Duan et al, 2016b, 2017), is used to calculate the entropy change. The method is more theoretically rigorous and time-saving than traditional Nmode method (Cong et al, 2017; Yan et al, 2017; Liu et al, 2018; Qiu et al, 2018; Song et al, 2018). …”