Non-native interactions in protein folding intermediates: Molecular dynamics simulations of hen lysozyme

Molecular dynamics simulations of protein denaturation can complement and e xtend experimental studies of protein folding by providing atomic-level str uctural information about conformational transitions and any conformational states along the unfolding pathway. Previous unfolding simulations of hen egg-white lysozyme have resulted in intermediate structures with an unfolde d alpha-domain and a structured beta-domain, which is inconsistent with exp eriment. In contrast, the beta-domain unfolded first in the two simulations presented here leaving a structured alpha-domain. Following this, intermed iate states were identified that differ with respect to the packing of the helices and the elements of non-native structure adopted. The non-native st ructure is critical for explaining many of the experimental observations. O verall, the pooled ensemble of these intermediates is in agreement with the experimental data for the major kinetic intermediate, suggesting that die kinetic intermediate may be made up of distinct, but rapidly interconvertin g, partially folded conformations distinguished primarily by differences in helix packing. (C) 1998 Academic Press.