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

S-adenosyl methionine (SAM) -dependent methyl transferases (MTases) are aubiquitous class of enzymes catalyzing dozens of essential life processes. Despite targeting a largespace of substrates with diverse intrinsic reactivity, SAM MTases have similar catalytic efficiency.While understanding of MTase mechanism has grown tremendously through integration ofstructural characterization, kinetic assays, and multiscale simulations, it remains elusive regardinghow 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 betterunderstand how the properties (i.e., electric field strength and active site volumes) of SAM MTaseshave been evolved to achieve similar catalytic efficiency towards substrates of different reactivity.We found that electric field strengths have largely evolved to make the target atom a better methylacceptor. For MTases that target RNA/DNA- and histone protein, our results suggest that electricfield strength accommodates hybridization state and variation in cavity volume trends withdiversity of substrate classes. Metal ions in SAM MTases contribute negatively to electric fieldstrength for methyl donation and enzyme scaffolds have evolved to offset these contributions.