Topography of funneled landscapes determines the thermodynamics and kinetics of protein folding

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-09, Vol.109 (39), p.15763-15768
• Main Authors: Wang, Jin, Oliveira, Ronaldo J, Chu, Xiakun, Whitford, Paul C, Chahine, Jorge, Han, Wei, Wang, Erkang, Onuchic, José N, Leite, Vitor B.P
• Format: Article
• Language: English
• Subjects: Biological Sciences; Energetics; Energy; Entropy; Enzyme kinetics; Flux density; Kinetics; Models, Chemical; Protein Folding; Proteins; Proteins - chemistry; roughness; Sloping terrain; Temperature; Thermodynamics; topography; Topology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1212842109

The energy landscape approach has played a fundamental role in advancing our understanding of protein folding. Here, we quantify protein folding energy landscapes by exploring the underlying density of states. We identify three quantities essential for characterizing landscape topography: the stabilizing energy gap between the native and nonnative ensembles δ E , the energetic roughness Δ E , and the scale of landscape measured by the entropy S . We show that the dimensionless ratio between the gap, roughness, and entropy of the system [Formula] accurately predicts the thermodynamics, as well as the kinetics of folding. Large Λ implies that the energy gap (or landscape slope towards the native state) is dominant, leading to more funneled landscapes. We investigate the role of topological and energetic roughness for proteins of different sizes and for proteins of the same size, but with different structural topologies. The landscape topography ratio Λ is shown to be monotonically correlated with the thermodynamic stability against trapping, as characterized by the ratio of folding temperature versus trapping temperature. Furthermore, Λ also monotonically correlates with the folding kinetic rates. These results provide the quantitative bridge between the landscape topography and experimental folding measurements.