Folding intermediate in the villin headpiece domain arises from disruption of a N-terminal hydrogen-bonded network.

摘要: The critical role of partially folded intermediates in protein misfolding and amyloid formation has sparked interest exploring factors that control the these metastable species. Recent NMR experiments reported a sparsely populated intermediate villin headpiece domain, which N-terminal subdomain is random coil-like under native conditions. Here we use continuous constant pH molecular dynamics simulations with replica-exchange sampling protocol to test hypothesis conformational state obtained by derived from solution structure represents putative unfolded. On basis unique titration behavior His41 as well structural dynamic properties this state, propose loss hydrogen bond between Nδ backbone carbonyl oxygen E14 leads inter-subdomain contacts partial disruption N-termina...