Publication Category: Conformational Free Energies

  • Evaluation of Conformational Changes in Diabetes-Associated Mutation in Insulin a Chain: A Molecular Dynamics Study.

    Proteins: Structure, Function, and Bioinformatics 83.4 (2015): 662-669.

    permanent neonatal-onset diabetes mellitus known as Mutant INS-gene induced Diabetes of Youth (MIDY) with insulin deficiency. To gain insights into the molecular basis of this diabetes-associated mutation, we perform molecular dynamics simulations in wild-type and mutant (CysA7 to Tyr or C(A7)Y) insulin A chain in aqueous solutions.

  • AWE-WQ: Fast-Forwarding Molecular Dynamics Using the Accelerated Weighted Ensemble

    Journal of chemical information and modeling 54.10 (2014): 3033-3043.

    high energy barriers trap the system in these states. Recently the weighted ensemble (WE) family of methods have emerged which can flexibly and efficiently sample conformational space without being trapped and allow calculation of unbiased rates.

  • Modeling Conformational Ensembles of Slow Functional Motions in Pin1-WW

    PLoS computational biology 6.12 (2010): e1001015.

    studies can map these dynamics. However, defining the network of inter-converting conformers that underlie the relaxation data remains generally challenging. Here, we combine NMR relaxation experiments with simulation to visualize networks of inter-converting conformers.

  • ATP-driven Non-equilibrium Activation of Kinase Clients by the Molecular Chaperone Hsp90

    Biophysical Journal 119.8 (2020): 1538-1549.

    The molecular chaperone 90-kDa heat-shock protein (Hsp90) assists the late-stage folding and activation of diverse types of protein substrates (called clients), including many kinases. Previous studies have established that the Hsp90 homodimer undergoes an ATP-driven cycle through open and closed conformations. Here I propose a model of client activation by Hsp90, which predicts that this

  • Molecular Simulations Minimally Restrained by Experimental Data

    The Journal of chemical physics 150.15 (2019): 154121.

    One popular approach to incorporating experimental data into molecular simulations is to restrain the ensemble average of observables to their experimental values. Here, I derive equations for the equilibrium distributions generated by restrained ensemble simulations and the corresponding expected values of observables. My results suggest a method to restrain simulations so that they generate distributions

  • Cochaperones Enable Hsp70 to Use ATP Energy for Non-Equilibrium Sta- bilization of Native Proteins

    Biophysical Journal 116.3 (2019): 339a.

    The heat shock protein 70 (Hsp70) chaperones, vital to the proper folding of proteins inside cells, consume ATP and require cochaperones in assisting pro- tein folding. It is unclear whether Hsp70 can utilize the free energy from ATP hydrolysis to fold a protein into a native state that is thermodynamically unsta- ble in the chaperone-free

  • The Hsp70 Interdomain Linker Is a Dynamic Switch That Enables Allosteric Communication Between Two Structured Domains

    Journal of Biological Chemistry 292.36 (2017): 14765-14774.

    Hsp70 molecular chaperones play key roles in cellular protein homeostasis by binding to exposed hydrophobic regions of incompletely folded or aggregated proteins. This crucial Hsp70 function relies on allosteric communication between two well-structured domains: an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD), which are tethered by an interdomain linker. ATP or ADP