dMSGB-IE: Computational Mutational Scanning for (de)Methylation Thermodynamics

The (de)methylation regulates the functional interactions between unstructured N-terminal of histone and other globular proteins. The multistate behavior of the methyl-substitution makes the situation complex, e.g., being mono-methylated, di-methylated, or tri-methylated. As a pivotal epigenetic marker, understanding its thermodynamic impact on protein-protein binding is crucial for the elucidation of the regulation mechanism of epigenetic modifications on target genes. To this aim, in this work we present a cost-effective free energy technique named computational (de)methylation scanning with generalized Born and interaction entropy (dMSGB-IE). Our regime is built on implicit-solvent-based end-point free energy techniques, and provides an efficient route to access the (de)methylation-induced affinity change with a screening power comparable to costlier alchemical free energy calculations. We use a batch of histone-reader recognition protein-protein complexes as illustrative cases, showing the capabilities and reliabilities of dMSGB-IE.