Hidden protein folding pathways in free-energy landscapes uncovered by network analysis

A network analysis is used to uncover hidden folding pathways in free-energy landscapes usually defined in terms of such arbitrary order parameters as root-mean-square deviation from the native structure, radius of gyration, etc. The analysis has been applied to molecular dynamics (MD) trajectories of the B-domain of staphylococcal protein A, generated with the coarse-grained united-residue (UNRES) force field in a broad range of temperatures (270K ≤ T ≤ 325K). Thousands of folding pathways have been identified at each temperature. Out of these many folding pathways, several most probable ones were selected for investigation of the conformational transitions during protein folding. Unlike other conformational space network (CSN) methods, a node in the CSN variant implemented in this work is defined according to the nativelikeness class of the structure, which defines the similarity of segments of the compared structures in terms of secondary-structure, contact-pattern, and local geometry, as well as the overall geometric similarity of the conformation under consideration to that of the reference (experimental) structure. Our previous findings, regarding the folding model and conformations found at the folding-transition temperature for protein A (Maisuradze et al., J. Am. Chem. Soc. 132, 9444, 2010), were confirmed by the conformational space network analysis. In the methodology and in the analysis of the results, the shortest path identified by using the shortest-path algorithm corresponds to the most probable folding pathway in the conformational space network.