Binding mechanism of inhibitors to p38α MAP kinase deciphered by using multiple replica Gaussian accelerated molecular dynamics and calculations of binding free energies. (July 2021)

• Record Type: Journal Article
• Authors: Chen, Jianzhong; Wang, Wei; Sun, Haibo; Pang, Laixue; Bao, Huayin
• Is Part Of: Computers in biology and medicine. Volume 134(2021)
• Publication Date: 2021-07
• Subjects: p38α MAP Kinase -- MR-GaMD simulation -- MM-GBSA -- Principal component analysis -- Hot spots; Medicine -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; 610.285
• DOI: 10.1016/j.compbiomed.2021.104485
• Languages: English
• ISSNs: 0010-4825

Abstract

Abstract: The p38α MAP Kinase has been an important target of drug design for treatment of inflammatory diseases and cancers. This work applies multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations and the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding mechanism of inhibitors L51, R24 and 1AU to p38α. Dynamics analyses show that inhibitor bindings exert significant effect on conformational changes of the active helix α2 and the conserved DFG loop. The rank of binding free energies calculated with MM-GBSA not only agrees well with that determined by the experimental IC50 values but also suggests that mutual compensation between the enthalpy and entropy changes can improve binding of inhibitors to p38α. The analyses of free energy landscapes indicate that the L51, R24 and 1AU bound p38α display a DFG-out conformation. The residue-based free energy decomposition method is used to evaluate contributions of separate residues to the inhibitor-p38α binding and the results imply that residues V30, V38, L74, L75, I84, T106, H107, L108, M109, L167, F169 and D168 can be utilized as efficient targets of potent inhibitors toward p38α. Graphical abstract: Inhibitor bindings induce multiple free energy valleys and conformational changes of p38α. Image 1 Highlights: MR-GaMD simulations are applied to enhance conformational sampling of p38α. Free energy landscapes are used to reveal energetic basis concerning conformational changes of p38α. Dynamics cross-correlation maps are utilized to probe correlated motions of p38α.