High-throughput Computational Investigation of Protein Electrostatics and Cavity for SAM-dependent Methyltransferases

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 the integration of structural characterization, kinetic assays, and multiscale simulations, it remains elusive how these enzymes have evolved to fit the diverse chemical needs of their respective substrates. In this work, we performed a high-throughput molecular modeling analysis of 91 SAM MTases to better understand how their properties (i.e., electric field [EF] strength and active site volumes) help achieve similar catalytic efficiency toward substrates of different reactivity. We found that EF strengths have largely adjusted to make the target atom a better methyl acceptor. For MTases that target RNA/DNA and histone proteins, our results suggest that EF strength accommodates formal hybridization state and variation in cavity volume trends with diversity of substrate classes. Metal ions in SAM MTases contribute negatively to EF strength for methyl donation and enzyme scaffolds tend to offset these contributions.