title: In silico construction of HK2-VDAC1 complex and investigating the HK2 binding-induced molecular gating mechanism of VDAC1.
abstract: Hexokinase 2 (HK2) binds to Voltage-Dependent Anion Channel 1 (VDAC1) on mitochondrial outer membrane (MOM) to facilitate a preferential access of ATP to HK2 for glycolysis, in order to maintain a constant energy source for cell proliferation in cancer especially. While previous studies have discovered that the VDAC1 N-terminal helix is responsible for regulating molecules from within mitochondria to cytoplasm, the molecular mechanism of how HK2 is able to regulate the ATP access remains elusive. We hereby propose a model for the HK2-VDAC1 association. The model is then subjected to molecular dynamics (MD) simulations, where we probe the effect of HK2 binding on the mobility of the VDAC1 N-terminal helix. Results from the simulations show that HK2 binding restricts the movement of the VDAC1 N-terminal helix. As a result, VDAC1 is kept in the open state most of the time and probably allows a constant supply of ATP to HK2 for glycolysis.
authors.affiliation: School of Physics and Engineering, Henan University of Science and Technology, Luoyang 471023, PR China. Electronic address: sunstar53@126.com.
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
authors.forename: Yew Mun
authors.initials: YM
authors.lastname: Yip
authors.affiliation: School of Physics and Engineering, Henan University of Science and Technology, Luoyang 471023, PR China.
authors.forename: Liben
authors.initials: L
authors.lastname: Li
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D006593:Hexokinase / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C494762:VDAC1 protein, human; D000255:Adenosine Triphosphate; D050995:Voltage-Dependent Anion Channel 1; C000609700:HK2 protein, human; D006593:Hexokinase
keywords: Glycolysis; Hexokinase 2; Mitochondrion; Molecular gate; Voltage-Dependent Anion Channel 1