|Name||Mr. Liwei Chang|
|Organization or Institution||University of Florida|
How protein G, L and their mutants fold
Liwei Chang, Alberto Perez
Department of Chemistry, University of Florida
Much of our understanding of folding mechanisms comes from interpretations of experimental ϕ and ψ value analysis – relating the differences in stability of the transition state ensemble (TSE) and folded state. We introduce a unified approach combining simulations and Bayesian inference to provide atomistic detail for the folding mechanism of protein G, L and their mutants. Protein G and L fold to similar topologies despite low sequence similarity, but differ in their folding pathways. A fast folding redesign of protein G, NuG2, switches folding pathways and folds through a similar pathway with protein L. A redesign of protein L also leads to faster folding, respecting the original folding pathway. Our Bayesian inference approach starts from the same prior on all systems and correctly identifies the folding mechanism for each of the four proteins – a success of the force field and sampling strategy. The approach is computationally efficient and correctly identifies the TSE and intermediate structures along the folding pathway in good agreement with experiments. We complement our findings by adaptive sampling MD combined with Markov State Model provide a kinetic model that confirms the more complex folding mechanism of protein G and its mutant.