Reactive molecular dynamics investigation of the first steps of coronavirus (COVID-19) viral-protein ligands fragment (SARS-CoV-2).

Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was first identified in the People's Republic of China and is characterized by infection of airway epithelial cells, frequently leading to severe acute respiratory syndrome and clinically diagnosed as severe human pneumonia. The primary targets of SARS-CoV-2 are lung cells, where viral-host interactions trigger extensive molecular and structural changes. In this work, we developed fully atomistic reactive molecular dynamics simulations to investigate the binding energies, binding atoms, and dynamic behavior of biological assemblies of viral protein-ligand fragments associated with SARS-CoV-2. The studied protein structures correspond to the PDB entries (6Y84), (5REH), (5REJ), (5REK), (5REN), (5REO), (5RF0), (5RGG), and (6LU7). All simulations were performed using the reactive force field ReaxFF implemented in the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS), enabling explicit treatment of bond formation and bond breaking processes. The molecular dynamics simulations were conducted at room temperature to analyze the dynamical behavior of viral protein ligands under realistic external conditions. Our results reveal that all classes of viral ligand proteins exhibit pronounced chemical reactivity, characterized by the spontaneous formation of new chemical bonds during thermal equilibration. Our reactive classical molecular dynamics (ReaxFF) simulations show that SARS-CoV-2 viral protein assemblies undergo significant chemical reactivity, forming both covalent (mainly C-C, C-N, and C-O) and non-covalent interactions. Newly formed covalent bonds exhibit lengths of 1.2-1.4 Å and average angles around 120°, consistent with sp2-like geometries that contribute to local nanostructural stabilization. Nanometric solvation analysis further reveals distinct hydration profiles, where 6Y84 exhibits a compact shell at 3.04 Å suggesting a "dry" catalytic pocket, while 6LU7 displays the most extended hydration influence and the highest hydrogen bond stability (avg. 78.88). Detailed analysis of the ReaxFF energy contributions, including bond, angle, and nonbonded interaction terms, demonstrates that the observed reactivities are energetically consistent and thermodynamically stable. The potential energy curves further confirm both the validity of the ReaxFF parameter set and the nanostructural stability of the viral protein-ligand fragments under ambient temperature conditions. These findings highlight the intrinsic mutability and reactivity of SARS-CoV-2 binding proteins at the nanoscale. The present theoretical results complement previous crystallographic and experimental studies and provide novel insights into nanostructural activity-reactivity relationships of viral fragments that remain inaccessible to current experimental techniques, thereby offering valuable perspectives for future antiviral research.