Discrete Kinetic Models from Funneled Energy Landscape Simulations

• Autores: Schafer, Nicholas P.; Hoffman, Ryan M. B.; Burger, Anat; Craig, Patricio Oliver; Komives, Elizabeth A.; Wolynes, Peter G.
• Año de publicación: 2012
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: folding; kinetics; discrete; energy landscape
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

A general method for facilitating the interpretation of computer simulations of protein folding with minimally frustrated energy landscapes is detailed and applied to a designed ankyrin repeat protein (4ANK). In the method, groups of residues are assigned to foldons and these foldons are used to map the conformational space of the protein onto a set of discrete macrobasins. The free energies of the individual macrobasins are then calculated, informing practical kinetic analysis. Two simple assumptions about the universality of the rate for downhill transitions between macrobasins and the natural local connectivity between macrobasins lead to a scheme for predicting overall folding and unfolding rates, generating chevron plots under varying thermodynamic conditions, and inferring dominant kinetic folding pathways. To illustrate the approach, free energies of macrobasins were calculated from biased simulations of a non-additive structure-based model using two structurally motivated foldon definitions at the full and half ankyrin repeat resolutions. The calculated chevrons have features consistent with those measured in stopped flow chemical denaturation experiments. The dominant inferred folding pathway has an "inside-out", nucleation-propagation like character.
Fil: Schafer, Nicholas P.. Rice University; Estados Unidos. University of California at San Diego; Estados Unidos
Fil: Hoffman, Ryan M. B.. University of California at San Diego; Estados Unidos. Rice University; Estados Unidos
Fil: Burger, Anat. University of California at San Diego; Estados Unidos. Rice University; Estados Unidos
Fil: Craig, Patricio Oliver. University of California at San Diego; Estados Unidos. Rice University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Komives, Elizabeth A.. University of California at San Diego; Estados Unidos
Fil: Wolynes, Peter G.. Rice University; Estados Unidos. University of California at San Diego; Estados Unidos