Constant pH Molecular Dynamics of Proteins in Explicit Solvent with Proton Tautomerism

摘要: pH is a ubiquitous regulator of biological activity, including protein-folding, protein-protein interactions, and enzymatic activity. Existing constant molecular dynamics (CPHMD) models that were developed to address questions related the pH-dependent properties proteins are largely based on implicit solvent models. However, known underestimate desolvation energy buried charged residues, increasing error associated with predictions involve internal ionizable residue important in processes like hydrogen transport electron transfer. Furthermore, discrete water ions cannot be modeled solvent, which systems membrane ion channels. We report an explicit framework multi-site λ-dynamics (CPHMD(MSλD)). In CPHMD(MSλD) framework, we performed seamless alchemical transitions between protonation tautomeric states using λ-dynamics, designed novel biasing potentials ensure physical end-states predominantly sampled. show simulations model realistic such as Hen-Egg White Lysozyme (HEWL), binding domain 2-oxoglutarate dehydrogenase (BBL) N-terminal ribosomal protein L9 (NTL9), pKa excellent agreement experimental values, RMSE ranging from 0.72 0.84 units. With recent development for nucleic acids, accurate modeling both major class biomolecules-proteins acids now possible.