NR APGY
AU Ding,F.; Borreguero,J.M.; Buldyrey,S.V.; Stanley,H.E.; Dokholyan,N.V.
TI Mechanism for the alpha-helix to beta-hairpin transition
QU Proteins 2003 Nov 1; 53(2): 220-8
PT journal article
AB The aggregation of alpha-helix-rich proteins into beta-sheet-rich amyloid fibrils is associated with fatal diseases, such as Alzheimer's disease and prion disease. During an aggregation process, protein secondary structure elements-alpha-helices-undergo conformational changes to beta-sheets. The fact that proteins with different sequences and structures undergo a similar transition on aggregation suggests that the sequence nonspecific hydrogen bond interaction among protein backbones is an important factor. We perform molecular dynamics simulations of a polyalanine model, which is an alpha-helix in its native state and observe a metastable beta-hairpin intermediate. Although a beta-hairpin has larger potential energy than an alpha-helix, the entropy of a beta-hairpin is larger because of fewer constraints imposed by the hydrogen bonds. In the vicinity of the transition temperature, we observe the interconversion of the alpha-helix and beta-sheet states via a random coil state. We also study the effect of the environment by varying the relative strength of side-chain interactions for a designed peptide-an alpha-helix in its native state. For a certain range of side-chain interaction strengths, we find that the intermediate beta-hairpin state is destabilized and even disappears, suggesting an important role of the environment in the aggregation propensity of a peptide.
MH Amino Acid Sequence; Computer Simulation; Hydrogen Bonding; Hydrophobicity; Models, Molecular; Peptides/chemistry; *Protein Structure, Secondary; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
AD Center for Polymer Studies, Department of Physics, Boston University, Boston, Massachusetts 02215, USA. fding@polymer.bu.edu
SP englisch
PO USA