Molecular dynamics simulation reveals how phosphorylation of tyrosine 26 of phosphoglycerate mutase 1 upregulates glycolysis and promotes tumor growth

// Yan Wang 1 , Wen-Sheng Cai 2 , Luonan Chen 3 , Guanyu Wang 1 1 Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China 2 Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin 300071, China 3 Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China Correspondence to: Luonan Chen, email: lnchen@sibs.ac.cn Guanyu Wang, email: wanggy@sustc.edu.cn Keywords: oncotarget, glycolysis, molecular dynamics simulation Received: June 29, 2016 Accepted: December 16, 2016 Published: January 05, 2017 ABSTRACT Phosphoglycerate mutase 1 (PGAM1) catalyzes the eighth step of glycolysis and is often found upregulated in cancer cells. To test the hypothesis that the phosphorylation of tyrosine 26 residue of PGAM1 greatly enhances its activity, we performed both conventional and steered molecular dynamics simulations on the binding and unbinding of PGAM1 to its substrates, with tyrosine 26 either phosphorylated or not. We analyzed the simulated data in terms of structural stability, hydrogen bond formation, binding free energy, etc. We found that tyrosine 26 phosphorylation enhances the binding of PGAM1 to its substrates through generating electrostatic environment and structural features that are advantageous to the binding. Our results may provide valuable insights into computer-aided design of drugs that specifically target cancer cells with PGAM1 tyrosine 26 phosphorylated.