Computational insights into the binding pattern of mitochondrial calcium uniporter inhibitor through homology modeling, molecular dynamics simulation, binding free energy prediction and density functional theory calculation

Na Duan; Zisen Gao; Baichun Hu; Dandan Ge; Wei Li; Tong Ye; Xiaohui Geng; Xiaodong Li

doi:10.1080/07391102.2019.1695674

Computational insights into the binding pattern of mitochondrial calcium uniporter inhibitor through homology modeling, molecular dynamics simulation, binding free energy prediction and density functional theory calculation

J Biomol Struct Dyn. 2020 Oct;38(17):5095-5107. doi: 10.1080/07391102.2019.1695674. Epub 2019 Nov 27.

Authors

Na Duan^{1

2}, Zisen Gao³, Baichun Hu³, Dandan Ge^{3

4}, Wei Li⁵, Tong Ye⁶, Xiaohui Geng⁷, Xiaodong Li¹

Affiliations

¹ Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, China.
² Department of Cardiology, The People's Hospital of Liaoning Province, Shenyang, China.
³ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
⁴ International Office, Shenyang Pharmaceutical University, Shenyang, China.
⁵ Yantai Branch of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Yantai, China.
⁶ College of Arts, Sciences, Northeast Agricultural University, Harbin, Chinaand.
⁷ School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.

PMID: 31755365
DOI: 10.1080/07391102.2019.1695674

Abstract

The mitochondrial calcium uniporter (MCU) is the critical protein of the inner mitochondrial membrane that is the primary mediator for calcium uptake into the mitochondrial matrix. Herein we built the optimal homology model of human MCU which was refined through all-atom molecular dynamics simulation. Then, the binding mode of known inhibitor was predicted through molecular docking method, along with molecular dynamics simulation and binding free energy calculation to verify the docking result and stability of the protein-inhibitor complex. Finally, density functional theory (DFT) calculation enhanced our understanding of the molecular interaction of MCU inhibitor. Our research would provide a deeper insight into the interactions between human MCU and its inhibitor, which boosts to develop novel therapy against MCU related disease.Communicated by Ramaswamy H. Sarma.

Keywords: Mitochondrial calcium uniporter; binding free energy calculation; density functional theory calculation; homology modeling; molecular dynamics simulation.

MeSH terms

Calcium / metabolism
Calcium Channels* / metabolism
Density Functional Theory
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation*

Substances

Calcium Channels
mitochondrial calcium uniporter
Calcium