# Publications by Type: Journal Article

2016
Z. Ren, Jiang, S., Zeng, Q., Ding, X., Bai, S., Wang, J., Luo, Y., Su, Z., Xuan, Y., Yao, B., Cisneros, F., and Zhang, K., “Effect of dietary canthaxanthin and 25-hydroxycholecalciferol supplementation on the performance of duck breeders under two different vitamin regimens,” J Anim Sci BiotechnolJ Anim Sci Biotechnol, vol. 7, pp. 2, 2016.Abstract
BACKGROUND: Dietary canthaxanthin (CX), 25-hydroxycholecalciferol (25-OH-D 3 ) and vitamins have been widely reported to be involved in productive and reproductive performance of broiler breeders. However, limited information is available for duck breeders. In this study, a total of 1,560 Cherry Valley SM3 duck breeder females and 312 males were used to assess if the addition of CX and 25-OH-D3 could increase the performance of duck breeders under two different dietary vitamin regimens. Four diets were used under a 2 x 2 factorial arrangement with 2 kinds of vitamin premixes (REGULAR and HIGH; HIGH premix had higher levels of all vitamins except K3 than REGULAR premix), and with or without the supplementation of the mixture of CX (6 mg/kg) and 25-OH-D3 (0.069 mg/kg). The ducks were fed ad libitum with pelleted diets based on corn-soybean meal from 38 to 77 wk of age. RESULTS: HIGH vitamin premix decreased malondialdehyde (MDA) level (P < 0.001) of egg yolk, increased hatchability of fertile eggs (P = 0.029), increased hatchability of total eggs (P = 0.029), and decreased serum protein carbonyl level (P = 0.037) of breeder males. The mixture of CX and 25-OH-D3 increased serum calcium of breeder females (P = 0.010), decreased the cracked egg rate (P = 0.001), increased the pigmentation of egg yolk (P < 0.001) and male bill (P < 0.001), and decreased MDA level of egg yolk (P < 0.001) and male serum (P = 0.034). Interactive effects were observed in cracked egg rate (P = 0.038), shell thickness (P = 0.011) and serum phosphorus (P = 0.026) of breeder females. HIGH vitamin premix together with the mixture of CX and 25-OH-D3 decreased cracked egg rate and increased shell thickness of duck breeders. Serum phosphorus was decreased in duck breeder females fed REGULAR vitamin premix without the addition of the CX and 25-OH-D3 mixture. CONCLUSIONS: Dietary HIGH vitamin premix increased antioxidant status of eggs and breeder males, and increased hatchability. The mixture of CX and 25-OH-D3 enhanced egg shell quality, and promoted pigmentation and antioxidant status of eggs and breeder males.
R. Qi, Wang, Q., and Ren, P., “General van der Waals potential for common organic molecules,” Bioorg Med ChemBioorg Med Chem, vol. 24, pp. 4911-4919, 2016.Abstract
This work presents a systematic development of a new van der Waals potential (vdW2016) for common organic molecules based on symmetry-adapted perturbation theory (SAPT) energy decomposition. The Buf-14-7 function, as well as Cubic-mean and Waldman-Hagler mixing rules were chosen given their best performance among other popular potentials. A database containing 39 organic molecules and 108 dimers was utilized to derive a general set of vdW parameters, which were further validated on nucleobase stacking systems and testing organic dimers. The vdW2016 potential is anticipated to significantly improve the accuracy and transferability of new generations of force fields for organic molecules.
T. S. Kaoud, WH Johnson, P. A., ND Ebelt, M Warthaka,, Micael Cano, S. R., Q Wang, Pengyu Ren, R. G., and Dalby, K. N., “Covalent inhibition of ERK docking interactions,” The FASEB Journal, vol. 30, no. 1, pp. 856.11-856.11, 2016.
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.
Q. Wang, Rackers, J. A., He, C., Qi, R., Narth, C., Lagardere, L., Gresh, N., Ponder, J. W., Piquemal, J. - P., and Ren, P., “General model for treating short-range electrostatic penetration in a molecular mechanics force field,” Journal of chemical theory and computation, vol. 11, pp. 2609–2618, 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.
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.
H. Torabifard, Starovoytov, O. N., Ren, P., and Cisneros, A. G., “Development of an AMOEBA water model using GEM distributed multipoles,” Theoretical Chemistry Accounts, vol. 134, pp. 101, 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,” J Chem Theory ComputJ Chem Theory Comput, vol. 11, pp. 2589-99, 2015.Abstract
In this article, we present a parallel implementation of point dipole-based polarizable force fields for molecular dynamics (MD) simulations with periodic boundary conditions (PBC). The smooth particle mesh Ewald technique is combined with two optimal iterative strategies, namely, a preconditioned conjugate gradient solver and a Jacobi solver in conjunction with the direct inversion in the iterative subspace for convergence acceleration, to solve the polarization equations. We show that both solvers exhibit very good parallel performances and overall very competitive timings in an energy and force computation needed to perform a MD step. Various tests on large systems are provided in the context of the polarizable AMOEBA force field as implemented in the newly developed Tinker-HP package, which is the first implementation of a polarizable model that makes large-scale experiments for massively parallel PBC point dipole models possible. We show that using a large number of cores offers a significant acceleration of the overall process involving the iterative methods within the context of SPME and a noticeable improvement of the memory management, giving access to very large systems (hundreds of thousands of atoms) as the algorithm naturally distributes the data on different cores. Coupled with advanced MD techniques, gains ranging from 2 to 3 orders of magnitude in time are now possible compared to nonoptimized, sequential implementations, giving new directions for polarizable molecular dynamics with periodic boundary conditions using massively parallel implementations.
R. Qi, Wang, L. P., Wang, Q., Pande, V. S., and Ren, P., “United polarizable multipole water model for molecular mechanics simulation,” J Chem PhysJ Chem Phys, vol. 143, pp. 014504, 2015.Abstract
We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3-5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water.
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.
Q. Wang, Rackers, J. A., He, C., Qi, R., Narth, C., Lagardere, L., N Gresh, Q Wang,, Ponder, J. W., Piquemal, J. P., and Ren, P., “General Model for Treating Short-Range Electrostatic Penetration in a Molecular Mechanics Force Field,” J Chem Theory ComputJ Chem Theory Comput, vol. 11, pp. 2609-2618, 2015.Abstract
Classical molecular mechanics force fields typically model interatomic electrostatic interactions with point charges or multipole expansions, which can fail for atoms in close contact due to the lack of a description of penetration effects between their electron clouds. These short-range penetration effects can be significant and are essential for accurate modeling of intermolecular interactions. In this work we report parametrization of an empirical charge-charge function previously reported (Piquemal J.-P.; J. Phys. Chem. A2003, 107, 10353) to correct for the missing penetration term in standard molecular mechanics force fields. For this purpose, we have developed a database (S101x7) of 101 unique molecular dimers, each at 7 different intermolecular distances. Electrostatic, induction/polarization, repulsion, and dispersion energies, as well as the total interaction energy for each complex in the database are calculated using the SAPT2+ method (Parker T. M.; J. Chem. Phys.2014, 140, 094106). This empirical penetration model significantly improves agreement between point multipole and quantum mechanical electrostatic energies across the set of dimers and distances, while using only a limited set of parameters for each chemical element. Given the simplicity and effectiveness of the model, we expect the electrostatic penetration correction will become a standard component of future molecular mechanics force fields.
M. Warthaka, Adelmann, C. H., Kaoud, T. S., Edupuganti, R., Yan, C., Johnson, W. H., J., Ferguson, S., Tavares, C. D., Pence, L. J., Anslyn, E. V., Ren, P., Tsai, K. Y., and Dalby, K. N., “Quantification of a Pharmacodynamic ERK End Point in Melanoma Cell Lysates: Toward Personalized Precision Medicine,” ACS Med Chem LettACS Med Chem Lett, vol. 6, pp. 47-52, 2015.Abstract
Protein kinases are mutated or otherwise rendered constitutively active in numerous cancers where they are attractive therapeutic targets with well over a dozen kinase inhibitors now being used in therapy. While fluorescent sensors have capacity to measure changes in kinase activity, surprisingly they have not been utilized for biomarker studies. A first-generation peptide sensor for ERK based on the Sox fluorophore is described. This sensor called ERK-sensor-D1 possesses high activity toward ERK and more than 10-fold discrimination over other MAPKs. The sensor can rapidly quantify ERK activity in cell lysates and monitor ERK pathway engagement by BRAF and MEK inhibitors in cultured melanoma cell lines. The dynamic range of the sensor assay allows ERK activities that have potential for profound clinical consequences to be rapidly distinguished.
C. Zhang, Lu, C., Wang, Q., Ponder, J. W., and Ren, P., “Polarizable Multipole-Based Force Field for Dimethyl and Trimethyl Phosphate,” J Chem Theory ComputJ Chem Theory Comput, vol. 11, pp. 5326-39, 2015.Abstract
Phosphate groups are commonly observed in biomolecules such as nucleic acids and lipids. Due to their highly charged and polarizable nature, modeling these compounds with classical force fields is challenging. Using quantum mechanical studies and liquid-phase simulations, the AMOEBA force field for dimethyl phosphate (DMP) ion and trimethyl phosphate (TMP) has been developed. On the basis of ab initio calculations, it was found that ion binding and the solution environment significantly impact both the molecular geometry and the energy differences between conformations. Atomic multipole moments are derived from MP2/cc-pVQZ calculations of methyl phosphates at several conformations with their chemical environments taken into account. Many-body polarization is handled via a Thole-style induction model using distributed atomic polarizabilities. van der Waals parameters of phosphate and oxygen atoms are determined by fitting to the quantum mechanical interaction energy curves for water with DMP or TMP. Additional stretch-torsion and angle-torsion coupling terms were introduced in order to capture asymmetry in P-O bond lengths and angles due to the generalized anomeric effect. The resulting force field for DMP and TMP is able to accurately describe both the molecular structure and conformational energy surface, including bond and angle variations with conformation, as well as interaction of both species with water and metal ions. The force field was further validated for TMP in the condensed phase by computing hydration free energy, liquid density, and heat of vaporization. The polarization behavior between liquid TMP and TMP in water is drastically different.
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.
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.
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.
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.