Computational Investigation of S781F Mutation-Induced Remodeling of the Staphylococcal Nuclease Domain-Containing Protein 1–Argonaute 2 Interface

MicroRNA (miRNA)-guided gene silencing depends on the accurate assembly and regulation of the RNA-induced silencing complex (RISC), in which Argonaute-2 (Ago2) interacts with accessory proteins to facilitate complex stability and catalytic activity. Staphylococcal nuclease domain-containing protein 1 (SND1) is an important component of the RISC and a transcriptional co-regulator implicated in multiple cancers; however, the structural consequences of disease-associated SND1 mutations remain poorly understood. In this study, an integrated computational workflow combining protein–protein docking, molecular dynamics simulations, and free energy analyses was employed to investigate the potential structural effects of the SND1 S781F mutation on the SND1–Ago2 interaction. The wild-type complex was predicted to maintain a stable interaction network involving the Tudor domain of SND1 and methylated arginine residues of Ago2. In contrast, the S781F substitution was associated with altered intermolecular hydrogen bonding patterns, reduced predicted interaction stability, increased structural flexibility, altered correlated residue motions, and a broader free energy landscape, suggesting a less stable protein–protein interface. Although the mutant complex sampled a larger number of distinct intermolecular hydrogen bond interactions, these interactions exhibited lower occupancies and reduced persistence than those in the wild-type complex. Collectively, these computational findings suggest that the S781F mutation could act as a potential modulator of the local physicochemical environment, interaction stability, and conformational dynamics of the SND1–Ago2 surface. This study provides atomistic insights into the structural consequences of the S781F mutation and establishes a computational framework for future experimental validation of its role in miRNA-mediated gene regulation and cancer biology.