Allosteric Braking and Thermodynamic Trapping of SERCA1a Pump Dynamics Induced by Lysine Acetylation at the Pro308 Hinge Region: An Exploratory Multi-Scale Framework

Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1a (SERCA1a) plays a pivotal role in intracellular calcium homeostasis by actively transporting Ca2+ ions across the sarcoplasmic reticulum membrane against steep concentration gradients. Post-translational modifications, particularly lysine acetylation within the P-domain, serve as critical regulatory switches; however, their atomistic mechanics remain incompletely understood. Here, through extensive all-atom molecular dynamics (MD) simulations utilizing the OBC2 implicit solvent model, principal component analysis (PCA), free energy landscape (FEL) mapping, dynamic cross-correlation matrix (DCCM) calculations, and root-mean-square fluctuation (RMSF) profiling, we elucidate the mechanistic dichotomy between the unmodified Apo state and the P-domain acetylated state of SERCA1a (PDB: 1WPG). Our findings demonstrate that while the Apo state exhibits substantial conformational plasticity (RMSD ≈ 0.65–0.75 nm, Pro308 RMSF ≈ 0.25 nm, P-domain Rg = 11.08 ± 0.05 nm, Global Rg = 11.64 ± 0.03 nm) and a continuous free-energy basin along PC1 (ranging from -125 to +75), acetylation imposes a severe structural constraint. Lysine acetylation reduces total backbone displacement (RMSD ≈ 0.35–0.40 nm), quenches Pro308 hinge dynamics by nearly 70% (RMSF = 0.0804 nm / 0.80 Å), and collapses the cytosolic P-domain into a compact conformational trap (Rg ≈ 7.46 nm, fluctuating locally between 7.44 and 7.50 nm). DCCM matrices reveal a transition from broad long-range correlated motions in Apo to fragmented anti-correlated domains under acetylation, with an average cross-correlation Mean Cij = -0.0108 near Pro308. Consequently, acetylation acts as a "molecular brake" and thermodynamic trap that locks the Pro308 mechanical hinge and abrogates the E1 ⇌ E2 functional cycle.