A computational insight into binding modes of inhibitors XD29, XD35, and XD28 to bromodomain-containing protein 4 based on molecular dynamics simulations. Issue 5 (4th April 2018)

• Record Type: Journal Article
• Authors: Su, Jing; Liu, Xinguo; Zhang, Shaolong; Yan, Fangfang; Zhang, Qinggang; Chen, Jianzhong
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 36:Issue 5(2018)
• Page Start: 1212
• Page End: 1224
• Publication Date: 2018-04-04
• Subjects: MD simulations -- bromodomain-containing protein 4 -- principal component analysis -- MM-PBSA; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2017.1317666
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract : In the current work, conformational changes of bromodomain-containing protein 4 (1) (BRD4-1) induced by bindings of inhibitors XD29 (57G), XD35 (57F), and XD28 (L28) were investigated using molecular dynamics (MD) simulations and principal component analysis. The results demonstrate that inhibitor bindings produce significant effect on the motion of ZA loop in BRD4-1. Moreover, to further study binding modes of three inhibitors to BRD4-1, binding free energies of inhibitors to BRD4-1 were also calculated using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The results indicate that van der Waals interactions are main factors to modulate inhibitor bindings. Energy decomposition and hydrogen bond analysis demonstrate that residues Pro82, Leu92, Asn140, and Ile146 play important roles in binding processes of inhibitors to BRD4-1. This study is not only helpful for better understanding function and internal dynamics of BRD4-1, but also can provide a theoretical basis for rational designs of effective anticancer drugs targeting BRD4-1.