Massively parallel molecular dynamics simulations of lysozyme unfolding

dynamics simulations of lysozyme unfolding R. Zhou M. Eleftheriou C.-C Hon R. S. Germain A. K. Royyuru B. J. Berne We have performed molecular dynamics simulations for a total duration of more than 10 ls (with most molecular trajectories being 1 ls in duration) to study the effect of a single mutation on hen lysozyme protein stability and denaturing, using a IBM Blue Gene/Le supercomputer. One goal of this study was to assess the use of certain force fields to reproduce experimental results of protein unfolding using thermal denaturing techniques. A second and more important goal was to gain microscopic insights into the mechanism of protein misfolding using both thermal and chemical denaturing techniques. We found that the thermal denaturing results were robust and reproducible with various force fields. The chemical denaturing results explained why the single-amino-acid mutation on residue Trp62 causes the disruption of long-range interactions in the tertiary structure. Simulation results revealed that the Trp62 residue was the key to a cooperative long-range interaction within the wild-type protein. Specifically, Trp62 acts as a bridge between two neighboring basic residues through a p-type H-bond or p-cation interaction to form an Arg-Trp-Arg ‘‘sandwich-like’’ structure. Our findings support the general conclusions of the experiment and provide an interesting molecular depiction of the disruption of the long-range interactions.