Role of the Protonation State on the Structure and Dynamics of Albumin

Human serum albumin undergoes reversible conformational transitions associated with ligand binding or pH changes. Among them, the neutral to base (N → B) transition occurring between pH 7 and pH 9 seems to be relevant for its function as a carrier. Unfortunately, a detailed atomic model for the B-form is still lacking, and several open questions remain concerning the charge distribution of the N-form. In this work, we report comparable molecular models for the N and B conformations that are built using continuum electrostatic calculations of pKa values and extended molecular dynamics (MD) simulations. Our computational models, which are critically assessed in terms of the available experimental observations relative to the N → B transition, reveal interesting similarities and differences between the N- and B-forms of HSA and highlight the importance of setting proper charge configurations in MD simulations.