CHIRALITY-DEPENDENT MODULATION OF DIMERIC PROTEIN-PROTEIN INTERACTIONS BY NANOPARTICLES: A MOLECULAR DYNAMICS STUDY

Protein-protein interactions are dynamically regulated by the molecular environment, and chiral nanomaterials may modulate them through stereochemistry and binding to specific protein surfaces. Here, we investigated how nanoparticle presence and chirality affect dimeric protein interactions using all-atom molecular dynamics simulations. Five protein dimers were simulated for 1 μs with CHARMM36 in GROMACS 2025.1 under three conditions: apo (protein only) and two identical CuS-penicillamine (Pen) nanoparticles (NPs)^[1] with L-Pen or D-Pen chirality, yielding 15 simulations. Temporal analyses in 100 ns windows evaluated protein-protein and protein-NP interaction energies, hydrogen bonding, residue contacts, RMSD, and radius of gyration, enabling comparisons at both interaction and structural levels. The simulations revealed strongly protein- and chirality-dependent responses. For Rac2-RhoGDI2, NP binding promoted structural stabilization: RMSD and radius of gyration decreased for both L- and D-NP, while protein-protein interactions became more favorable and hydrogen bonding increased. Residue contacts remained concentrated in the same dimer interface regions, although contact fractions and rankings varied, indicating local rearrangements within a persistent interface. For Cathepsin X, NP binding increased RMSD while radius of gyration remained unchanged, indicating conformational rearrangement without major changes in global compactness. Mitochondrial branched-chain amino acid aminotransferase (BCAT2) and TACE-TIMP-3 maintained high structural stability, with only minor changes in RMSD and radius of gyration. In BCAT2, L-NP produced the most favorable chain-chain interaction, whereas D-NP was more favorable in TACE-TIMP-3 and increased hydrogen bonding. Contacts in TACE-TIMP-3 were highly persistent, particularly in TIMP-3, where a conserved CYS-THR-CYS-SER interface region remained highly contacted after NP binding. For Fis1, both L- and D-NP reduced RMSD and radius of gyration while weakening chain-chain interactions, indicating structural stabilization without strengthening the dimer interface. Overall, chiral CuS-Pen NPs modulated dimeric protein interactions in a strongly system-dependent manner. Depending on protein architecture and NP chirality, NP binding promoted interface stabilization, induced internal conformational rearrangements, or stabilized the protein without strengthening the dimer interface. These findings highlight the joint role of protein architecture and nanoparticle chirality in determining the dynamic response of protein dimers to nanomaterial binding.

[1] Gao et al. Proc. Natl. Acad. Sci. U. S. A. 2024;121(13).