dMSGB-IE: Computational mutational scanning for (de)methylation thermodynamics

The (de)methylation regulates the functional interactions between the unstructured N-terminal of histones and other globular proteins. The multistate behavior of methyl-substitution makes the situation complex; for example, 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 first use a batch of histone-reader recognition protein-protein complexes as illustrative cases, showing the capabilities and reliabilities of dMSGB-IE. Then, we augment the method with the integrative structure prediction tool AlphaFold 3, providing a fully computational workflow for fast estimation of (de)methylation free energies. Based on a batch of testing systems, we validate the practical applicability and highlight the predictive power of the promising integrative modeling workflow.