QM/MM Analysis of Transition States and Transition State Analogues in Metalloenzymes

TitleQM/MM Analysis of Transition States and Transition State Analogues in Metalloenzymes
Publication TypeBook Chapter
Year of Publication2016
AuthorsRoston, D, Cui, Q
EditorVoth, GA
Volume577
Pagination213-250
PublisherElsevier Academic Press Inc
CitySan Diego
ISBN Number0076-6879<br/>978-0-12-805347-8
KeywordsALKALINE-PHOSPHATASE SUPERFAMILY, Biochemical Research Methods, Biochemistry & Molecular Biology, BIOMOLECULAR SIMULATION, CATALYTIC ANTIBODIES, CYTOCHROME-C-OXIDASE, ENZYMATIC-REACTIONS, FORCE-FIELD, FREE-ENERGY CALCULATIONS, Mathematical & Computational Biology, MOLECULAR-DYNAMICS SIMULATIONS, NUCLEOTIDE, PYROPHOSPHATASE/PHOSPHODIESTERASE, QUANTUM MECHANICS/MOLECULAR MECHANICS, WAR MJS, 1985, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, V107, P3902
Abstract

Enzymology is approaching an era where many problems can benefit from computational studies. While ample challenges remain in quantitatively predicting behavior for many enzyme systems, the insights that often come from computations are an important asset for the enzymology community. Here we provide a primer for enzymologists on the types of calculations that are most useful for mechanistic problems in enzymology. In particular, we emphasize the integration of models that range from small active-site motifs to fully solvated enzyme systems for cross-validation and dissection of specific contributions from the enzyme environment. We then use a case study of the enzyme alkaline phosphatase to illustrate specific application of the methods. The case study involves examination of the binding modes of putative transition state analogues (tungstate and vanadate) to the enzyme. The computations predict covalent binding of these ions to the enzymatic nucleophile and that they adopt the trigonal bipyramidal geometry of the expected transition state. By comparing these structures with transition states found through free energy simulations, we assess the degree to which the transition state analogues mimic the true transition states. Technical issues worth treating with care as well as several remaining challenges to quantitative analysis of metalloenzymes are also highlighted during the discussion.

DOI10.1016/bs.mie.2016.05.016