The role of the unfolded state in hairpin stability.
The effects of a T3S mutation on the stability of a 3:5 beta-hairpin forming peptide (YITNSNGTWT) are investigated. Molecular dynamics simulations in explicit water indicate that the wild-type peptide forms a stable hairpin whereas the T3S mutant does not, in agreement with the experimental data. Thermodynamic integration calculations for the mutation of Thr to Ser suggest that the free-energy changes in the folded state are small, but the corresponding changes in the unfolded state are large and favorable. One of the main reasons for the difference appears to be the formation of a stable cluster involving the Tyr1 and Ser3 hydroxyl groups and their interaction with the C-terminal carboxylate group, which was observed after unfolding of the T3S mutant. Further analysis of the side-chain preferences of Thr and Ser indicate that the corresponding cluster in the wild-type peptide is unstable due to the high preference of the Thr chi1 dihedral for g+ states, which appeared to be incompatible with formation of a stable cluster. The results suggest that one should consider the nature of the unfolded state when attempting to fully explain the effects of mutations on hairpin stability.
Lei
Hongxing
H
Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506-3702, USA.
Smith
Paul E
PE
D055592:Biophysical Phenomena; D001703:Biophysics; D003198:Computer Simulation; D008958:Models, Molecular; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D012694:Serine / Q000737:chemistry; D013816:Thermodynamics; D013912:Threonine / Q000737:chemistry; D013997:Time Factors
D010455:Peptides; D013912:Threonine; D012694:Serine