Structural insights into the two sequential folding transition states of the PB1 domain of NBR1 from Φ value analysis and biased molecular dynamics simulations.
The PB1 domain of NBR1 folds via a single pathway mechanism involving two sequential energy barriers separated by a high-energy intermediate. The structural ensemble representing each of the two transition states (TS1 and TS2) has been calculated using experimental Φ values and biased molecular dynamics simulations. Both TS1 and TS2 represent compact states (β(TS1) = 0.71, and β(TS2) = 0.93) but are defined by quite different distributions of Φ values, degrees of structural heterogeneity, and nativelike secondary structure. TS1 forms a heterogeneous ensemble of dynamic structures, representing a global collapse of the polypeptide chain around a set of weak nativelike contacts. In contrast, TS2 has a high proportion of nativelike secondary structure, which is reflected in an extensive distribution of high Φ values. Two snapshots along the folding pathway of the PB1 domain reveal insights into the malleability, the solvent accessibility, and the timing of nativelike core packing that stabilizes the folded state.
Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
Ping
P
Chen
Clare-Louise
CL
Evans
Jonathan D
JD
Hirst
Mark S
MS
Searle
D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; C549756:NBR1 protein, human; D011506:Proteins