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Unfolding of hen egg lysozyme by molecular dynamics simulations at 300K: Insight into the role of the interdomain interface
Author(s) -
Gilquin Bernard,
Guilbert Christophe,
Perahia David
Publication year - 2000
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 - 10.1002/1097-0134(20001001)41:1<58::aid-prot90>3.0.co;2-3
Subject(s) - lysozyme , molecular dynamics , chemistry , folding (dsp implementation) , crystallography , protein folding , kinetics , chemical physics , helix (gastropod) , biophysics , protein structure , ww domain , computational chemistry , physics , biology , biochemistry , ecology , quantum mechanics , snail , gene , electrical engineering , engineering
We present the results of two 1.2 ns molecular dynamics (MD) unfolding simulations on hen egg lysozyme in water at 300K, performed using a new procedure called PEDC (Path Exploration With Distance Constraints). This procedure allows exploration of low energy structures as a function of increasing RMSD from the native structure, and offers especially the possibility of extensive exploration of the conformational space during the initial unfolding stages. The two independent MD simulations gave similar chronology of unfolding events: disruption of the active site, kinking of helix C, partial unfolding of the three‐stranded β‐sheet to a two‐stranded sheet (during which the helices A, B, and D remain to a great extent native), and finally unfolding of the β‐domain and partial unfolding of the α‐domain in which hydrophobic clusters persist. We show particularly that the loss of hydrophobic contacts between the β‐sheet turn residues Leu55 and Ile56 and the hydrobic patch of the α‐domain destabilizes the β‐domain and leads to its unfolding, suggesting that the correct embedding of these residues in the α‐β interface may constitute the rate limiting step in folding. These results are in accord with experimental observations on the folding/unfolding behavior of hen egg lysozyme at room temperature. They would also explain the loss of stability and the tendency to aggregation observed for the mutant Leu55Thr, and the slow refolding kinetics observed in the analogous amyloidogenic variant of human lysozyme. Proteins 2000;41:58–74. © 2000 Wiley‐Liss, Inc.