title: Study of the Villin headpiece folding dynamics by combining coarse-grained Monte Carlo evolution and all-atom molecular dynamics.
abstract: The folding mechanism of the Villin headpiece (HP36) is studied by means of a novel approach which entails an initial coarse-grained Monte Carlo (MC) scheme followed by all-atom molecular dynamics (MD) simulations in explicit solvent. The MC evolution occurs in a simplified free-energy landscape and allows an efficient selection of marginally-compact structures which are taken as viable initial conformations for the MD. The coarse-grained MC structural representation is connected to the one with atomic resolution through a "fine-graining" reconstruction algorithm. This two-stage strategy is used to select and follow the dynamics of seven different unrelated conformations of HP36. In a notable case the MD trajectory rapidly evolves towards the folded state, yielding a typical root-mean-square deviation (RMSD) of the core region of only 2.4 A from the closest NMR model (the typical RMSD over the whole structure being 4.0 A). The analysis of the various MC-MD trajectories provides valuable insight into the details of the folding and mis-folding mechanisms and particularly about the delicate influence of local and nonlocal interactions in steering the folding process.
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.
authors.forename: Giacomo M S
authors.initials: GM
authors.lastname: De Mori
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
authors.forename: Cristian
authors.initials: C
authors.lastname: Micheletti
mesh_terms: D000465:Algorithms; D020816:Amino Acid Motifs; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D002645:Chickens; D003198:Computer Simulation; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D009010:Monte Carlo Method; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D040901:Proteomics / Q000379:methods*; D012984:Software; D013816:Thermodynamics; D013997:Time Factors