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Biophys J. 2016 Apr 26;110(8):1716-1719. doi: 10.1016/j.bpj.2016.03.026.

Markov State Models and tICA Reveal a Nonnative Folding Nucleus in Simulations of NuG2.

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Department of Chemistry, Stanford University, Stanford, California.
Department of Chemistry, Stanford University, Stanford, California; SIMBIOS NIH Center for Biomedical Computation, Stanford University, Stanford, California.
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:


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.

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