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Interplay between hydrophobic cluster and loop propensity in β‐hairpin formation: A mechanistic study
Author(s) -
Colombo Giorgio,
De Mori Giacomo M.S.,
Roccatano Danilo
Publication year - 2003
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.0227203
Subject(s) - chemistry , hydrophobic effect , molecular dynamics , cluster (spacecraft) , sequence (biology) , chemical physics , peptide , protein secondary structure , crystallography , diagonal , side chain , protein structure , peptide sequence , amino acid , biophysics , computational chemistry , geometry , biochemistry , organic chemistry , mathematics , computer science , programming language , polymer , biology , gene
We investigated the structural determinants of the stability of a designed β‐hairpin containing a natural hydrophobic cluster from the protein GB1 and a D‐Pro‐Gly turn forming sequence. The results of our simulations shed light on the factors leading to an ordered secondary structure in a model peptide: in particular, the importance of the so‐called diagonal interactions in forming a stable hydrophobic nucleus in the β‐hairpin, together with the more obvious lateral interactions, is examined. With the use of long timescale MD simulations in explicit water, we show the role of diagonal interactions in driving the peptide to the correct folded structure (formation of the hydrophobic core with Trp 2, Tyr 4, and Phe 9 in the first stages of refolding) and in keeping it in the ensemble of folded conformations. The combination of the stabilizing effects of the D‐Pro‐Gly turn sequence and of the hydrophobic nucleus formation thus favors the attainment of an ordered secondary structure compatible with the one determined experimentally. Moreover, our data underline the importance of the juxtapositions of the side chains of amino acids not directly facing each other in the three‐dimensional structure. The combination of these interactions forces the peptide to sample a nonrandom portion of the conformational space, as can be seen in the rapid collapse to an ordered structure in the refolding simulation, and shows that the unfolded state can be closely correlated to the folded ensemble of structures, at least in the case of small model peptides.