Journal Title
Title of Journal: J Mol Model
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Abbravation: Journal of Molecular Modeling
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Publisher
Springer Berlin Heidelberg
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Authors: Qing Li Xiaoqiang Huang Yushan Zhu
Publish Date: 2014/06/17
Volume: 20, Issue: 7, Pages: 2314-
Abstract
Optimization to identify the global minimum energy conformation sequence in in silico enzyme design is computationally nondeterministic polynomialtime NPhard with the search time growing exponentially as the number of design sites increases This drawback forces the modeling of proteinligand systems to adopt discrete amino acid rotamers and ligand conformers as well as continuum solvent treatment of the environment however such compromises produce large numbers of false positives in sequence selection In this report cephalosporin acylase which catalyzes the hydrolytic reaction of cephalosporin C to 7aminocephalosporanic acid was used to investigate the dynamic features of activesitetransitionstate complex structures using molecular dynamics MD simulations to potentially eliminate false positives The molecular docking between cephalosporin C and wild type acylase N176 and its eight mutants showed that the ratelimiting step in the hydrolytic reaction of cephalosporin C is the acylation process MD simulations of the activesitetransitionstate complex structures of the acylation processes for N176 and its eight mutants showed that the geometrical constraints between catalytic residues and small molecule transition states are always well maintained during the 20 ns simulation for mutants with higher activities and more hydrogen bonds between binding residues and functional groups of the ligand side chain in the active pocket are formed for mutants with higher activities The conformations of the ligand transition states were changed greatly after the simulation This indicates that the hydrogen bond network between the ligand and protein could be improved to enhance the activity of cephalosporin C acylase in subsequent designThis work was supported financially by the National Natural Science Foundation of China Grant Numbers 20976093 21276136 and the National High Technology Research and Development 863 Program of China Grant Number 2012AA021204 This work was also supported partly by a NSFCDFG joint project Grant Number 21311130420 between China and Germany for international cooperation and exchange Discussions with Prof Juergen Pleiss and Mr Sven P Benson from the University of Stuttgart were greatly appreciated by all authors
Keywords:
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