The early stage of folding of villin headpiece subdomain observed in a 200-nanosecond fully solvated molecular dynamics simulation - PubMed (original) (raw)

The early stage of folding of villin headpiece subdomain observed in a 200-nanosecond fully solvated molecular dynamics simulation

Y Duan et al. Proc Natl Acad Sci U S A. 1998.

Abstract

A new approach in implementing classical molecular dynamics simulation for parallel computers has enabled a simulation to be carried out on a protein with explicit representation of water an order of magnitude longer than previously reported and will soon enable such simulations to be carried into the microsecond time range. We have used this approach to study the folding of the villin headpiece subdomain, a 36-residue small protein consisting of three helices, from an unfolded structure to a molten globule state, which has a number of features of the native structure. The time development of the solvation free energy, the radius of gyration, and the mainchain rms difference from the native NMR structure showed that the process can be seen as a 60-nsec "burst" phase followed by a slow "conformational readjustment" phase. We found that the burial of the hydrophobic surface dominated the early phase of the folding process and appeared to be the primary driving force of the reduction in the radius of gyration in that phase.

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Figures

Figure 1

Figure 1

Ribbon representations of the unfolded (a) and the native (c) structures, and the snapshots at 85 nsec (b), at 104 nsec (d), and at 182 nsec (e), generated by using University of California at San Francisco’s

midasplus

. rmsds from the native state are given in the figure.

Figure 2

Figure 2

Rγ and the mainchain rmsd from the native structure as a function of time. The straight lines represent the Rγ of the starting structure (upper line) and the native structure (lower line).

Figure 3

Figure 3

Helical content measured by the mainchain φ-ψ angle (−60 ± 30, −40 ± 30) from 10,000 snapshots (20 psec intervals). (Left) The average over the trajectory. The shaded bars represent the residues that are helical in the NMR structure. (Right) The fractional native helical content (i.e., those presented in both the native and the simulated structures divided by the total in the native structure) as a function of time.

Figure 4

Figure 4

(a) Fractional native contacts, Q, as a function of time. The native contacts were measured as the number of neighboring residues presented in the native structure. Residues are taken to be in contact if any of the atom pairs (including both sidechain and mainchain atoms) are closer than 2.8 Å, excluding residues i and i+1, which always have the contacts through mainchain atoms. Fractional native contact is the number of total native contacts presented in the simulated structure divided by the number of native contacts in the native structure. (b) SFE of the protein as a function of time. The upper dashed line represents the SFE of the starting structure, and the lower dotted line represents that of the native structure. The parameters are those by Eisenberg and McLachlan (43), (i.e., 0.0163, −0.00637, 0.02114, −0.02376, −0.05041, in kcal/mole/Å2, for the surface areas of nonpolar, polar, sulfur, charged oxygen, and charged nitrogen, respectively).

Figure 4

Figure 4

(a) Fractional native contacts, Q, as a function of time. The native contacts were measured as the number of neighboring residues presented in the native structure. Residues are taken to be in contact if any of the atom pairs (including both sidechain and mainchain atoms) are closer than 2.8 Å, excluding residues i and i+1, which always have the contacts through mainchain atoms. Fractional native contact is the number of total native contacts presented in the simulated structure divided by the number of native contacts in the native structure. (b) SFE of the protein as a function of time. The upper dashed line represents the SFE of the starting structure, and the lower dotted line represents that of the native structure. The parameters are those by Eisenberg and McLachlan (43), (i.e., 0.0163, −0.00637, 0.02114, −0.02376, −0.05041, in kcal/mole/Å2, for the surface areas of nonpolar, polar, sulfur, charged oxygen, and charged nitrogen, respectively).

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