Revised AMBER Parameters for Bioorganic Phosphates

Abstract

We report AMBER force field parameters for biological simulations involving phosphorylation of serine, threonine or tyrosine. The initial parameters used RESP fitting for the atomic partial charges and standard values for all other parameters such as Lennard-Jones coefficients. These were refined with the aid of a thermodynamic cycle consisting of experimentally determined pKa values, solvation energies from molecular dynamics free energy simulations, and gas phase basicities from QM calculations. A polarization energy term was included to account for the charge density change between the gas-phase and solution, and solvation free energies were determined using thermodynamic integration. Parameter adjustment is required to obtain consistent thermodynamic results with better balanced electrostatic interactions between water and the phosphate oxygens. To achieve this we modified the phosphate oxygen radii. A thermodynamically consistent parameter set can be derived for monoanions and requires an increase of the van der Waals phosphate oxygen radii of approximately 0.09 Å. Larger, residue-specific radii appear to be needed for dianions. The revised parameters developed here should be of particular interest for environments where simulations of multiple protonation states may be of interest.

Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

“…Incorporation of backbone flexibility as sampled by MD simulations can therefore improve the performance of induced-fit docking in MOE. Previous studies have found that protein conformation sampling from MD simulations can improve the performance of virtual screening, which is consistent with our results [44][45][46][47][48].…”

Highly sampled tetranucleotide and tetraloop motifs enable evaluation of common RNA force fields

“…These simulations show the UUCG loop conformation and dynamics on longer timescales and not only help to assess and validate the force field performance, but show that results obtained with the CPU and GPU versions of the PMEMD code behave similarly and also that similar results are seen with the specialized Anton supercomputer (Shaw Steinbrecher et al (2012). e Yildirim et al (2011).…”

Small Details Matter: The 2′-Hydroxyl as a Conformational Switch in RNA

“…19,20 All calculations were performed using the parm99 force field 21,22 supplemented with the bsc0 23 and chiOL3 24,25 modifications for RNA; some control simulations were performed with a local experimental RNA version of the parmbsc1 forcefield. 26 Electroneutrality was achieved by adding K + and extra K + Cl -to generate a 150 mM concentration (taking Dang's parameters [27][28][29] to represent ions). US calculations were performed to determine the free energy associated with S↔N conformational transition in a protein-RNA (MIWI PAZ domain bound to RNA; PDB ID 2XFM model 6) complex in the wild type, where Lys316 is in the vicinity of O2', and a mutant protein, where Lys316 is substituted by an alanine (K316A mutant).…”

“…In addition to the previous parametrization, a second 265 fitting was performed considering a specific modification of the Lennard-Jones potential 266 (increase in the sigma parameter) between the phosphate oxygen atoms and : i-the ribose 267 O2', O3' atoms, and ii-the amine nitrogen of the base (N6 in A, N2 in G and N4 in C), 268 herein called "parmbsc0chiOL3vdW". This correction to the Lennard Jones potential isS9 based on the AMBER parameters revision for organic phosphates proposed by 270 Steinbrecher et al, 28 which was recently shown to improve the description of RNA 271 tetranucleotides. 29 In the present work, instead of including a general Lennard-Jones 272 correction affecting the interaction between the phosphate oxygen atoms and all other 273 atoms in the system, the specific terms affecting only the atoms mentioned above were 274 corrected (see Supplementary Methods 5 section for the parmed.py script).…”