TY - JOUR T1 - Using Steered Molecular Dynamics to Predict and Assess Hsp70 Substrate-Binding Domain Mutants that Alter Prion Propagation A1 - Xu, Linan A1 - Hasin, Naushaba A1 - Shen, Manli A1 - He, Jianwei A1 - Xue, Youlin A1 - Zhou, Xiaohong A1 - Perrett, Sarah A1 - Song, Youtao A1 - Jones, Gary W. Y1 - 2013/01/31 N2 - Author Summary Direct non-covalent interactions between protein substrates and molecular chaperones play crucial roles in the protein folding process. [PSI+] is a prion of the yeast Saccharomyces cerevisiae, which is formed by mis-folding of the native Sup35 protein in a process analogous to formation of prions in mammals. While much genetic data exists showing a clear role for Hsp70 in prion propagation, biochemical data has yet to provide a clear link to how Hsp70 functions in prion propagation or how some Hsp70 mutants successfully impair in vivo propagation of prions. This paper employs a novel simulation method termed “steered molecular dynamics” to explore the different types and amounts of non-covalent interactions between wild type and mutated Hsp70, with a model substrate. Extrapolating the in silico data allowed us to decipher how a mutant Hsp70 impairs yeast prion propagation and allows us to predict other Hsp70 mutants that should behave in the same manner and to test these predictions in a yeast-based system. Our computational data shows that increasing the binding affinity of Hsp70 for substrate is one way of impairing prion propagation, a proposal that correlates very well with previous experimental genetic data. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 9 IS - 1 UR - https://doi.org/10.1371/journal.pcbi.1002896 SP - e1002896 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1002896 ER -