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Assessing the acid–base and conformational properties of histidine residues in human prion protein (125–228) by means of pK a calculations and molecular dynamics simulations
Author(s) -
Langella Emma,
Improta Roberto,
Crescenzi Orlando,
Barone Vincenzo
Publication year - 2006
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20979
Subject(s) - protonation , histidine , chemistry , molecular dynamics , titration , tautomer , crystallography , computational chemistry , titration curve , protein structure , prion protein , stereochemistry , amino acid , biochemistry , organic chemistry , medicine , ion , disease , pathology
A thorough 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 multi‐tautomer electrostatic calculations, average titration curves have been built for all titratable residues, using the whole bundles of NMR structures determined 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 pK a 's of His140 and His177 are ≈7.0, whereas those of His155 and His187 are < 5.5. 10‐ns long molecular dynamics simulations have been performed on five different models, corresponding to the most significant combinations of histidine protonation states. A critical comparison between the available NMR structures and our computational results (1) confirms that His155 and His187 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. Proteins 2006. © 2006 Wiley‐Liss, Inc.