title: Interplay of charge distribution and conformation in peptides: comparison of theory and experiment.
abstract: We assessed the correlation between charge distribution and conformation of flexible peptides by comparing the theoretically calculated potentiometric-titration curves of two model peptides, Ac-Lys5-NHMe (a model of poly-L-lysine) and Ac-Lys-Ala11-Lys-Gly2-Tyr-NH2 (P1) in water and methanol, with the experimental curves. The calculation procedure consisted of three steps: (i) global conformational search of the peptide under study using the electrostatically driven Monte Carlo (EDMC) method with the empirical conformational energy program for peptides (ECEPP)/3 force field plus the surface-hydration (SRFOPT) or the generalized Born surface area (GBSA) solvation model as well as a molecular dynamics method with the assisted model building and energy refinement (AMBER)99/GBSA force field; (ii) reevaluation of the energy in the pH range considered by using the modified Poisson-Boltzmann approach and taking into account all possible protonation microstates of each conformation, and (iii) calculation of the average degree of protonation of the peptide at a given pH value by Boltzmann averaging over conformations. For Ac-Lys5-NHMe, the computed titration curve agrees qualitatively with the experimental curve of poly-L-lysine in 95% methanol. The experimental titration curves of peptide P1 in water and methanol indicate a remarkable downshift of the first pK(a) value compared to the values for reference compounds (n-butylamine and phenol, respectively), suggesting the presence of a hydrogen bond between the tyrosine hydroxyl oxygen and the H(epsilon) proton of a protonated lysine side chain. The theoretical titration curves agree well with the experimental curves, if conformations with such hydrogen bonds constitute a significant part of the ensemble; otherwise, the theory predicts too small a downward pH shift.
authors.affiliation: Faculty of Chemistry, University of Gdańsk, Sobieskiego 18, 80-952 Gdańsk, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Makowska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bagińska
authors.forename: F
authors.initials: F
authors.lastname: Kasprzykowski
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Vila
authors.forename: Anna
authors.initials: A
authors.lastname: Jagielska
authors.forename: Adam
authors.initials: A
authors.lastname: Liwo
authors.forename: Lech
authors.initials: L
authors.lastname: Chmurzyński
authors.forename: Harold A
authors.initials: HA
authors.lastname: Scheraga
mesh_terms: D004563:Electrochemistry; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D011199:Potentiometry; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D009842:Oligopeptides; D010455:Peptides