title: Structural Determinants of Misfolding in Multidomain Proteins.
abstract: Recent single molecule experiments, using either atomic force microscopy (AFM) or Förster resonance energy transfer (FRET) have shown that multidomain proteins containing tandem repeats may form stable misfolded structures. Topology-based simulation models have been used successfully to generate models for these structures with domain-swapped features, fully consistent with the available data. However, it is also known that some multidomain protein folds exhibit no evidence for misfolding, even when adjacent domains have identical sequences. Here we pose the question: what factors influence the propensity of a given fold to undergo domain-swapped misfolding? Using a coarse-grained simulation model, we can reproduce the known propensities of multidomain proteins to form domain-swapped misfolds, where data is available. Contrary to what might be naively expected based on the previously described misfolding mechanism, we find that the extent of misfolding is not determined by the relative folding rates or barrier heights for forming the domains present in the initial intermediates leading to folded or misfolded structures. Instead, it appears that the propensity is more closely related to the relative stability of the domains present in folded and misfolded intermediates. We show that these findings can be rationalized if the folded and misfolded domains are part of the same folding funnel, with commitment to one structure or the other occurring only at a relatively late stage of folding. Nonetheless, the results are still fully consistent with the kinetic models previously proposed to explain misfolding, with a specific interpretation of the observed rate coefficients. Finally, we investigate the relation between interdomain linker length and misfolding, and propose a simple alchemical model to predict the propensity for domain-swapped misfolding of multidomain proteins.
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Tian
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Best
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D031541:Fluorescence Resonance Energy Transfer; D007700:Kinetics; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D017510:Protein Folding; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D020080:Tandem Repeat Sequences
chemical_list: D011506:Proteins