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Method to Predict Crowding Effects by Postprocessing Molecular Dynamics Trajectories: Application to the Flap Dynamics of HIV-1 Protease
Qin, S., D.D.L. Minh, J.A. McCammon, H.X. Zhou
J. Phys. Chem. Letters 1, 107-110 (2010)
The internal dynamics of proteins inside of cells may be affected by
the crowded intracellular environments. Here, we test a novel approach to
simulations of crowding, in which simulations in the absence of crowders are
postprocessed to predict crowding effects, against the direct approach of simulations
in the presence of crowders. The effects of crowding on the flap dynamics of
HIV-1 protease predicted by the postprocessing approach are found to agree well
with those calculated by the direct approach. The postprocessing approach
presents distinct advantages over the direct approach in terms of accuracy and
speed and is expected to have broad impact on atomistic simulations of macromolecular
crowding.
The gates of ion channels and enzymes
Zhou, H.X., J.A. McCammon
Trends Biochem. Sci. in press (2010)
Identification of triazinoindol-benzimidazolones as nanomolar inhibitors of the Mycobacterium tuberculosis enzyme TDP-6-deoxy-D-xylo-4-hexopyranosid-4-ulose 3,5-epimerase (RmlC)
Sivendran, S., V. Jones, D. Sun, Y. Wang, A.E. Grzegorzewicz, M.S. Scherman, A.D. Napper, J.A. McCammon, R.E. Lee, S.L. Diamond,, M. McNeil
Bioorg. & Med. Chem. in press (2010)
Solutions to a Reduced Poisson–Nernst–Planck System and Determination of Reaction Rates
Li, B., B. Lu, Z. Wang, J.A. McCammon
A Multidimensional Strategy to Detect Polypharmacological Targets in the Absence of Structural and Sequence Homology
Durrant, J., R.E. Amaro, L. Xie, M.D. Urbaniak, M.A.J. Ferguson, A. Haapalainen, Z. Chen, A.M. Di Guilmi, F. Wunder, P.E. Bourne, J.A. McCammon
PLoS Comp. Biol. in press (2010)
Enhanced Conformational Space Sampling Improves the Prediction of Chemical Shifts in Proteins
Markwick, P., C. Cervantes, B. Abel, E. Komives, M. Blackledge, J.A. McCammon.
J. Amer. Chem. Soc. in press (2010)
A biased-potential molecular dynamics simulation method, accelerated molecular dynamics (AMD),was combined with the chemical shift prediction algorithm SHIFTX to calculate 1-H^N , 15-N, 13-Calpha, 13-Cbeta and 13-C' chemical shifts of the ankyrin repeat protein I-kappa-B-alpha (residues 67-206), the primary inhibitorof nuclear factor kappa-B. Free-energy-weighted molecular ensembles were generated over a range of acceleration levels, affording systematic enhancement of the conformational space sampling of the protein. We have found that the predicted chemical shifts, particularly for the 15-N, 13-Calpha, and 13-Cbeta nuclei, improve substantially with enhanced conformational space sampling up to an optimal acceleration level. Significant improvement in the predicted chemical shift data coincides with those regions of the protein that exhibit backbone dynamics on longer time scales. Interestingly, the optimal acceleration level for reproduction of the chemical shift data has previously been shown to best reproduce the experimental residual dipolar coupling (RDC) data for this system, as both chemical shift data and RDCs report on an ensemble and time average in the millisecond range.
Large conformational changes in proteins: signaling and other functions
Grant, B.J., A.A. Gorfe, J.A. McCammon
Curr. Opin. Struct. Biol. in press (2010)
Guanine and adenine nucleotide triphosphatases, such as Ras proteins and protein kinases, undergo large conformational changes upon ligand binding in the course of their functions. New computer simulation methods have combined with experimental studies to deepen our understanding of these phenomena. In particular, a ‘conformational selection’ picture is emerging, where alterations in the relative populations of pre- existing conformations can best describe the conformational switching activity of these important proteins.
Coupling Constant pH Molecular Dynamics with Accelerated Molecular Dynamics
Williams, S.L., C.A.F. de Oliveira, J.A. McCammon
J. Chem. Theory Comput. in press (2010)
An extension of the constant pH method originally implemented by Mongan et al. (J. Comput. Chem. 2004, 25, 2038-2048) is proposed in this study. This adapted version of the method couples the constant pH methodology with the enhanced sampling technique of accelerated molecular dynamics, in an attempt to overcome the sampling issues encountered with current standard constant pH molecular dynamics methods. Although good results were reported by Mongan et al. on application of the standard method to the hen egg-white lysozyme (HEWL) system, residues which possess strong interactions with neighboring groups tend to converge slowly, resulting in the reported consistencies for predicted pKa values, as highlighted by the authors. The application of the coupled method described in this study to the HEWL system displays improvements over the standard version of the method, with the improved sampling leading to faster convergence and producing pKa values in closer agreement to those obtained experimentally for the more slowly converging residues.
Kinetics of diffusion-controlled enzymatic reactions with charged substrates
Lu, B.Z., J.A. McCammon