title: A Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Binary Complex of Escherichia coli 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase with MgATP.
abstract: 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes the first reaction in the folate biosynthetic pathway. Comparison of its X-ray and nuclear magnetic resonance structures suggests that the enzyme undergoes significant conformational change upon binding to its substrates, especially in three catalytic loops. Experimental research has shown that, in its binary form, even bound by analogues of MgATP, loops 2 and 3 remain rather flexible; this raises questions about the putative large-scale induced-fit conformational change of the HPPK-MgATP binary complex. In this work, long-time all-atomic molecular dynamics simulations were conducted to investigate the loop dynamics in this complex. Our simulations show that, with loop 3 closed, multiple conformations of loop 2, including the open, semiopen, and closed forms, are all accessible to the binary complex. These results provide valuable structural insights into the details of conformational changes upon 6-hydroxymethyl-7,8-dihydropterin (HP) binding and biological activities of HPPK. Conformational network analysis and principal component analysis related to the loops are also discussed.
authors.affiliation: Institute of Biophysics and Department of Physics, Central China Normal University , Wuhan 430079, P. R. China.
authors.forename: Kaifu
authors.initials: K
authors.lastname: Gao
authors.affiliation: Institute of Biophysics and Department of Physics, Central China Normal University , Wuhan 430079, P. R. China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences , Wuhan 430071, P. R. China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Yang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D017854:Diphosphotransferases / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology*; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011622:Pterins / Q000378:metabolism*
chemical_list: C492818:6-hydroxymethyl-7,8-dihydropterin; D011622:Pterins; D000255:Adenosine Triphosphate; D017854:Diphosphotransferases