Assessing the acid-base and conformational properties of histidine residues in human prion protein (125-228) by means of pKa calculations and molecular dynamics simulations

A through study of the acid-base behavior of the four histidines and the other titratable residues of the structured domain of human prion protein (125-228) is presented. By using multitautomer electrostatic calcns., av. titrn. curves have been built for all titratable residues, using the whole bundles of NMR structures detd. at pH 4.5 and 7.0. According to our results, (1) only histidine residues are likely to be involved in the first steps of the pH-driven conformational transition of prion protein; (2) the pKa's of His-140 and His-177 are ≈ 7.0, whereas those of His-155 and His-187 are <5.5. 10-Ns long mol. dynamics simulations have been performed on five different models, corresponding to the most significant combinations of histidine protonation states. A crit. comparison between the available NMR structures and our computational results (1) confirms that His-155 and His-187 are the residues whose protonation is involved in the conformational rearrangement of huPrP in mildly acidic condition, and (2) shows how their protonation leads to the destructuration of the C-terminal part of HB and to the loss of the last turn of HA that represent the crucial microscopic steps of the rearrangement.