Estudo computacional da estabilidade termodinâmica de complexos de nanopartículas quirais e proteínas

Abstract

Molecular recognition at the interface between nanoparticles (NPs) and biomolecules depends on the structural and stereochemical organization of the interacting surfaces. However, the molecular mechanisms by which surface chirality modulates protein interactions remain only partially understood. This study investigated the influence of the chirality of trimanganese tetroxide nanoparticles functionalized with mannonic acid (Mn3O4-man) on their interaction with human serum albumin (HSA). Molecular dynamics simulations were performed to investigate systems containing apo-HSA and NPs with L- and D-chiral configurations. The trajectories were analyzed in terms of interaction energies, hydrogen bonds, intermolecular contacts, and structural and conformational parameters of the protein. The results showed that the interaction with HSA strongly depends on the chiral configuration of the nanoparticle surface, as only the L-NPs were able to establish stable and energetically favorable interactions with the protein. The D-NPs exhibited only transient contacts and interaction energy profiles close to zero, without the formation of persistent bound states. Spatial analysis of the interactions revealed that chiral recognition occurred locally, with Domain III of HSA, particularly the region corresponding to the Sudlow II site, being the only region capable of sustaining a stable interface with the L-NPs, mainly involving residues Lys538, Ala539, Lys541, and Glu542. The interaction energies and contact maps suggest that interface stabilization depends on the formation of a cooperative network of spatially complementary interactions, consistent with the concept of an interfacial “chiral footprint.” Conformational analyses indicated that persistent interaction with the L-NP induces localized dynamic changes, particularly in Domain III, without compromising the overall structural stability of HSA. The RMSD, RMSF, and radius of gyration results are consistent with a two-step recognition mechanism involving initial recognition driven by stereochemical compatibility between the surfaces, followed by local conformational adaptations consistent with an induced-fit mechanism. Overall, the results demonstrate that surface chirality acts as a selective structural factor in biomolecular recognition, influencing the affinity, temporal persistence, and spatial organization of protein-nanoparticle interactions. These findings contribute to the mechanistic understanding of nano-biomolecular interactions and provide a basis for the rational design of nanomaterials with enhanced biomolecular selectivity.