Markov State Models and tICA Reveal a Nonnative Folding Nucleus in Simulations of NuG2.
After reanalyzing simulations of NuG2-a designed mutant of protein G-generated by Lindorff-Larsen et al. with time structure-based independent components analysis and Markov state models as well as performing 1.5 ms of additional sampling on Folding@home, we found an intermediate with a register-shift in one of the β-sheets that was visited along a minor folding pathway. The minor folding pathway was initiated by the register-shifted sheet, which is composed of solely nonnative contacts, suggesting that for some peptides, nonnative contacts can lead to productive folding events. To confirm this experimentally, we suggest a mutational strategy for stabilizing the register shift, as well as an infrared experiment that could observe the nonnative folding nucleus.
Department of Chemistry, Stanford University, Stanford, California.
Christian R
CR
Schwantes
Department of Chemistry, Stanford University, Stanford, California; SIMBIOS NIH Center for Biomedical Computation, Stanford University, Stanford, California.
Diwakar
D
Shukla
Department of Chemistry, Stanford University, Stanford, California; Biophysics Program, Stanford University, Stanford, California; Structural Biology, Stanford University, Stanford, California; Department of Computer Science, Stanford University, Stanford, California. Electronic address: pande@stanford.edu.
Vijay S
VS
Pande
D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics; D008390:Markov Chains; D056004:Molecular Dynamics Simulation; D009154:Mutation; D000072757:Protein Conformation, beta-Strand; D017510:Protein Folding; D013223:Statistics as Topic
D001426:Bacterial Proteins; C034284:IgG Fc-binding protein, Streptococcus