Publications

2015
Y. Shi, Ren, P., Schnieders, M., and Piquemal, J. - P., “Polarizable force fields for biomolecular modeling,” Reviews in Computational Chemistry, vol. 28, pp. 51–86, 2015.
F. Lipparini, Lagardère, L., Raynaud, C., Stamm, B., Cancès, E., Mennucci, B., Schnieders, M., Ren, P., Maday, Y., and Piquemal, J. - P., “Polarizable molecular dynamics in a polarizable continuum solvent,” Journal of chemical theory and computation, vol. 11, pp. 623–634, 2015.
L. Lagardere, Lipparini, F., Polack, E., Stamm, B., Cances, E., Schnieders, M., Ren, P., Maday, Y., and Piquemal, J. - P., “Scalable evaluation of polarization energy and associated forces in polarizable molecular dynamics: II. Toward massively parallel computations using smooth particle Mesh Ewald,” Journal of chemical theory and computation, vol. 11, pp. 2589–2599, 2015.
Q. Wang, Edupuganti, R., Tavares, C. D., Dalby, K. N., and Ren, P., “Using docking and alchemical free energy approach to determine the binding mechanism of eEF2K inhibitors and prioritizing the compound synthesis,” Front Mol BiosciFront Mol Biosci, vol. 2, pp. 9, 2015.Abstract
A-484954 is a known eEF2K inhibitor with submicromolar IC50 potency. However, the binding mechanism and the crystal structure of the kinase remains unknown. Here, we employ a homology eEF2K model, docking and alchemical free energy simulations to probe the binding mechanism of eEF2K, and in turn, guide the optimization of potential lead compounds. The inhibitor was docked into the ATP-binding site of a homology model first. Three different binding poses, hypothesis 1, 2, and 3, were obtained and subsequently applied to molecular dynamics (MD) based alchemical free energy simulations. The calculated relative binding free energy of the analogs of A-484954 using the binding pose of hypothesis 1 show a good correlation with the experimental IC50 values, yielding an r (2) coefficient of 0.96 after removing an outlier (compound 5). Calculations using another two poses show little correlation with experimental data, (r (2) of less than 0.5 with or without removing any outliers). Based on hypothesis 1, the calculated relative free energy suggests that bigger cyclic groups, at R1 e.g., cyclobutyl and cyclopentyl promote more favorable binding than smaller groups, such as cyclopropyl and hydrogen. Moreover, this study also demonstrates the ability of the alchemical free energy approach in combination with docking and homology modeling to prioritize compound synthesis. This can be an effective means of facilitating structure-based drug design when crystal structures are not available.
2014
P. Ren, Mu, X., Wang, Q., and Xia, Z., “Development of AMOEBA Force Field with Advanced Electrostatics,” in Molecular Modeling at the Atomic Scale, CRC Press, 2014, pp. 102–127.
Z. Xia, Wang, Q., Mu, X., and Ren, P., “Development of AMOEBA Force Field with Advanced Electrostatics,” Methods and Applications in Quantitative Biology. Taylor & Francis: New York, NY2014, 2014.
C. D. J. Tavares, Ferguson, S. B., Giles, D. H., Wang, Q., Wellmann, R. M., O'Brien, J. P., Warthaka, M., Brodbelt, J. S., Ren, P., and Dalby, K. N., “The molecular mechanism of eukaryotic elongation factor 2 kinase activation,” Journal of Biological Chemistry, pp. jbc–M114, 2014.
A. Marjolin, Gourlaouen, C., Clavaguéra, C., Ren, P. Y., Piquemal, J. - P., and Dognon, J. - P., “Hydration gibbs free energies of open and closed shell trivalent lanthanide and actinide cations from polarizable molecular dynamics,” Journal of molecular modeling, vol. 20, pp. 2471, 2014.
M. Warthaka, Adelmann, C. H., Kaoud, T. S., Edupuganti, R., Yan, C., Johnson Jr, W. H., Ferguson, S., Tavares, C. D., Pence, L. J., Anslyn, E. V., and others,Quantification of a pharmacodynamic ERK end point in melanoma cell lysates: toward personalized precision medicine,” ACS medicinal chemistry letters, vol. 6, pp. 47–52, 2014.
A. K. Devkota, Edupuganti, R., Yan, C., Shi, Y., Jose, J., Wang, Q., Kaoud, T. S., Cho, E. J., Ren, P., and Dalby, K. N., “Reversible Covalent Inhibition of eEF-2K by Carbonitriles,” Chembiochem, vol. 15, pp. 2435–2442, 2014.
H. Shen, Li, Y., Ren, P., Zhang, D., and Li, G., “Anisotropic coarse-grained model for proteins based on Gay–Berne and electric multipole potentials,” Journal of chemical theory and computation, vol. 10, pp. 731–750, 2014.
K. M. Eckes, Mu, X., Ruehle, M. A., Ren, P., and Suggs, L. J., “$\beta$ Sheets not required: Combined experimental and computational studies of self-assembly and gelation of the ester-containing analogue of an Fmoc-dipeptide hydrogelator,” Langmuir, vol. 30, pp. 5287–5296, 2014.
Z. Xia, Wang, Q., Mu, X., and Ren, P., “Development of AMOEBA Force Field with Advanced Electrostatics,” Molecular Modeling at the Atomic Scale: Methods and Applications in Quantitative Biology, pp. 83, 2014.
J. R. Abella, Cheng, S. Y., Wang, Q., Yang, W., and Ren, P., “Hydration free energy from orthogonal space random walk and polarizable force field,” Journal of chemical theory and computation, vol. 10, pp. 2792–2801, 2014.
Q. Wang, Park, J., Devkota, A. K., Cho, E. J., Dalby, K. N., and Ren, P., “Identification and validation of novel PERK inhibitors,” Journal of chemical information and modeling, vol. 54, pp. 1467–1475, 2014.
X. Mu, Wang, Q., Wang, L. - P., Fried, S. D., Piquemal, J. - P., Dalby, K. N., and Ren, P., “Modeling organochlorine compounds and the $\sigma$-hole effect using a polarizable multipole force field,” The Journal of Physical Chemistry B, vol. 118, pp. 6456–6465, 2014.
F. Lipparini, Lagardère, L., Stamm, B., Cancès, E., Schnieders, M., Ren, P., Maday, Y., and Piquemal, J. - P., “Scalable evaluation of polarization energy and associated forces in polarizable molecular dynamics: I. toward massively parallel direct space computations,” Journal of Chemical Theory and Computation, vol. 10, pp. 1638–1651, 2014.
R. Edupuganti, Wang, Q., Tavares, C. D. J., Chitjian, C. A., Bachman, J. L., Ren, P., Anslyn, E. V., and Dalby, K. N., “Synthesis and biological evaluation of pyrido [2, 3-d] pyrimidine-2, 4-dione derivatives as eEF-2K inhibitors,” Bioorganic & medicinal chemistry, vol. 22, pp. 4910–4916, 2014.
C. D. J. Tavares, Ferguson, S. B., Giles, D. H., Wang, Q., Wellmann, R. M., O'Brien, J. P., Warthaka, M., Brodbelt, J. S., Ren, P., and Dalby, K. N., “

The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation

,” Journal of Biological Chemistry, vol. 289, pp. 23901-23916 (PMCID: PMC4156036), 2014.
H. Shen, Li, Y., Ren, P., Zhang, D., and Li, G., “An Anisotropic Coarse-Grained Model for Proteins Based On Gay-Berne and Electric Multipole Potentials,” Journal of Chemical Theory and Computation, vol. 10, pp. 731–750, 2014.

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