Application of Classical and Quantum Mechanics Methods for Structural and Dynamical Analysis of the Cellular Prion Protein (PrPC) with Potential Molecular Targets

Protein–protein interactions play a key role in regulating biological processes. Understanding these mechanisms is crucial for elucidating molecular events involved in disease development and normal cellular function. In this context, the multifunctional Cellular Prion Protein (PrP^C in its normal form and PrP^Sc in its infectious form) is notable for its involvement in both physiological and pathological processes, interacting with a lot of molecular partners. However, its conformational and functional dynamics during such interactions remain poorly understood. This study aims to evaluate the structural and dynamic behavior of PrP^C in complex with potential molecular ligands, employing classical and quantum computational methods. The PrP^C structure, including its intrinsically disordered N-terminal region, was modeled using AlphaFold 3. Protein–ligand interactions were explored via Molecular Docking using the ClusPro server to predict the most favorable binding poses. The time evolution of atomic interactions was assessed using Molecular Dynamics simulations, with both coarse-grained (GROMACS 2022.4) and atomistic (NAMD3) approaches. Quantum mechanical analyses were employed to investigate the frontier molecular orbitals, particularly HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital), to assess their spatial distribution and relevance to electron donor–acceptor regions within the protein complexes. Calculations were performed using MOPAC, and visualizations were generated via PRIMoRDiA (Macromolecular Reactivity Descriptors Access). The results revealed stable structural complexes and interaction-dependent reactivity at the protein–ligand interfaces. These findings contribute to a better understanding of the functional and biological dynamics of PrP^C in the context of its molecular partners.