NDLI: A method for predicting individual residue contributions to enzyme specificity and binding-site energies, and its application to MTH1

Content Provider	Springer Nature Link
Author	Stewart, James J. P.
Copyright Year	2016
Abstract	A new method for predicting the energy contributions to substrate binding and to specificity has been developed. Conventional global optimization methods do not permit the subtle effects responsible for these properties to be modeled with sufficient precision to allow confidence to be placed in the results, but by making simple alterations to the model, the precisions of the various energies involved can be improved from about ±2 kcal mol−1 to ±0.1 kcal mol−1. This technique was applied to the oxidized nucleotide pyrophosphohydrolase enzyme MTH1. MTH1 is unusual in that the binding and reaction sites are well separated—an advantage from a computational chemistry perspective, as it allows the energetics involved in docking to be modeled without the need to consider any issues relating to reaction mechanisms. In this study, two types of energy terms were investigated: the noncovalent interactions between the binding site and the substrate, and those responsible for discriminating between the oxidized nucleotide 8-oxo-dGTP and the normal dGTP. Both of these were investigated using the semiempirical method PM7 in the program MOPAC. The contributions of the individual residues to both the binding energy and the specificity of MTH1 were calculated by simulating the effect of mutations. Where comparisons were possible, all calculated results were in agreement with experimental observations. This technique provides fresh insight into the binding mechanism that enzymes use for discriminating between possible substrates.
Starting Page	1
Ending Page	19
Page Count	19
File Format	PDF
ISSN	16102940
Journal	Journal of Molecular Modeling
Volume Number	22
Issue Number	11
e-ISSN	09485023
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2016-10-06
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	PM7 Noncovalent interactions Docking Binding Enzyme specificity MTH1 Nucleotide hydrolysis Computer Applications in Chemistry Molecular Medicine Computer Application in Life Sciences Characterization and Evaluation of Materials Theoretical and Computational Chemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Physical and Theoretical Chemistry Computational Theory and Mathematics Catalysis Inorganic Chemistry Computer Science Applications

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