High-Throughput Computational Investigation of Protein Electrostatics and Cavity for SAM-Dependent Methyltransferases.

Abstract

S-adenosyl methionine (SAM) -dependent methyl transferases (MTases) are a ubiquitous class of enzymes catalyzing dozens of essential life processes. Despite targeting a large space of substrates with diverse intrinsic reactivity, SAM MTases have similar catalytic efficiency. While understanding of MTase mechanism has grown tremendously through integration of structural characterization, kinetic assays, and multiscale simulations, it remains elusive regarding how these enzymes have evolved to fit the diverse chemical needs of their respective substrates. In this work, we performed a high-throughput computational analysis of 91 SAM MTases to better understand how the properties (i.e., electric field strength and active site volumes) of SAM MTases help achieve similar catalytic efficiency towards substrates of different reactivity. We found that electric field strengths have largely adjusted to make the target atom a better methyl acceptor. For MTases that target RNA/DNA- and histone protein, our results suggest that electric field strength accommodates formal hybridization state and variation in cavity volume trends with diversity of substrate classes. Metal ions in SAM MTases contribute negatively to electric field strength for methyl donation and enzyme scaffolds tend to offset these contributions. This article is protected by copyright. All rights reserved.