A fast empirical GAFF compatible partial atomic charge assignment scheme for modeling interactions of small molecules with biomolecular targets

Abstract

We report here a new and fast approach [Transferable Partial Atomic Charge Model (TPACM4)-upto four bonds] for deriving the partial atomic charges of small molecules for use in protein/DNA-ligand docking and scoring. We have created a look-up table of 5302 atom types to cover the chemical space of C, H, O, N, S, P, F, Cl, and Br atoms in small molecules together with their quantum mechanical RESP fit charges. The atom types defined span diverse plausible chemical environments of each atom in a molecule. The partial charge on any atom in a given molecule is then assigned by a reference to the look-up table. We tested the sensitivity of the TPACM4 partial charges in estimates of hydrogen bond dimers energies, solvation free energies and protein-ligand binding free energies. An average error ±1.11 kcal/mol and a correlation coefficient of 0.90 is obtained in the calculated protein-ligand binding free energies vis-à-vis an RMS error of ±1.02 kcal/mol and a correlation coefficient of 0.92 obtained with RESP fit charges in comparison to experiment. Similar accuracies are realized in predictions of hydrogen bond energies and solvation free energies of small molecules. For a molecule containing 50-55 atoms, the method takes on the order of milliseconds on a single processor machine to assign partial atomic charges. The TPACM4 programme has been web-enabled and made freely accessible at http://www.scfbio-iitd.res.in/software/drugdesign/charge.jsp.

Quantum mechanics approaches to drug research in the era of structural chemogenomics

“…70,71 Correlation coefficients between predicted and experimental binding free energy values were 0.89, 0.90, 0.91, and 0.92 for MMFF, TPACM4, AM1-BCC, 72 and RESP, respectively: an improvement that is not dramatic, but is nevertheless encouraging due to its consistency with the employed level of theoretical difficulty.…”

Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol

“…AMBER99-ILDN force-field [39,40,41] was chosen to describe protein topology. The General Amber Force Field, GAFF, [42,43] and TIP3P model [44] were employed for TFE and water molecules, respectively. Partial charges of TFE were obtained using the AM1-BCC method [45,46].…”

Molecular Electrostatic Potentials from Invariom Point Charges

“…These charges are used alongside other force-field parameters for modeling and molecular dynamics simu- www.chemphyschem.org lations, for example, in programs like Amber, [28] Charmm, [29] or Gromacs. [31] We follow the philosophy but not the procedural details of this transferable partial atomic charge model (TPACM4), and provide restrained fit to the electrostatic potential [24] (RESP) point charges derived from the model compounds in the generalized invariom database [6] in this article. Partitioning of as ystem into smaller fragments more amenable to computation is required as soon as larger (> 150 atoms) or even macromolecular systems, for example, metalloproteins or supramolecular structures/assemblies, are studied.…”

“…[31] Similar to the web version of the utility PDB2PQR, [38,39] implementation is via aw eb server that turns a pdb file, typically of an organic molecule, into a pqr file. To avoid computations altogether,t he TPACM4 lookup table for RESP charges was developed.…”