Force Field Development

Overview

In the context of molecular modeling, a force field (a special case of energy functions or interatomic potentials; not to be confused with force field in classical physics) refers to the functional form and parameter sets used to calculate the potential energy of a system of atoms or coarse-grained particles in molecular mechanics and molecular dynamics simulations. The parameters of the energy functions may be derived from experiments in physics or chemistry, calculations in quantum mechanics, or both.

All-atom force fields provide parameters for every type of atom in a system, including hydrogen, while united-atom interatomic potentials treat the hydrogen and carbon atoms in each methyl group (terminal methyl) and each methylene bridge as one interaction center. Coarse-grained potentials, which are often used in long-time simulations of macromolecules such as proteins, nucleic acids, and multi-component complexes, provide even cruder representations for higher computing efficiency. By calculating all the energies (bond, angle, torsion, electrostatic, VDW, etc.), the analytical first and second derivatives of each atom in a biological system, we can simulate how each atom moves in a system, the chemical reaction path, spectra, correlation of structure and function.

Our Focus

Warshel and his colleagues, Levitt and Lifson, developed the Consistent Force Field (CFF) method ^{[1] [2] [3]} and the corresponding computer programs that are the basis of current molecular modeling methods (CHARMM, AMBER, GROMOS, etc.).

MOLARIS, which has been evolved from Warshel's initial computer program, is a package that integrates two main modules, ENZYMIX and POLARIS, and a set of general utilities which are incorporated in the module ANALYZE. These three modules are interconnected in order to provide a robust and powerful tool for investigating the function of biological molecules. The program is particularly effective in studies of enzymatic reactions ^[4] and in evaluating electrostatic energies in proteins ^[5]. MOLARIS-XG is an extension of the MOLARIS package to coarse-grain (CG) calculations ^[6].

MOLARIS can be used as a complete tool for the investigation of the structure-function relationships in enzymes and other biomolecules. It has also been used for:

1. Propagating molecular dynamics (MD) trajectories for various purposes.
2. Evaluating free energy profiles for reactions in water and in enzymes, by means of combinations of empirical valence bond (EVB) potential energy surfaces with free energy perturbation/umbrella sampling (FEP/US) approaches.
3. Obtaining solvation free energies of molecules in water or in the protein and evaluate the solvation energy of part of a macromolecule.
4. Performing fully automated pKa calculations for ionizable residues in the protein and obtain titration curves of all the residues within the protein.
5. The pKa calculations are done using the linear response approximation (LRA) method using automatically generated protein configurations for the charged and uncharged states of the given residues.
6. Obtaining absolute binding free energies of ligands - not only enthalpy or scoring functions. This again is done with the powerful LRA approach.
7. Calculating REDOX potentials in proteins. Here our approach has been shown to be particularly powerful in very challenging cases including iron sulfur proteins.
8. Studying ion permeation through ion channels. This allows one to explore the effect of voltage on conductance and gating within the actual structure of ion channels.
9. Calculating electric fields and molecular electrostatic potentials in proteins.
10. Calculating the effect of ionic strength.
11. Evaluating entropic effects on binding and obtain activation entropies for enzymatic reactions.
12. Performing advanced QM/MM calculations.
13. Evaluating absolute folding energies.
14. Calculating the effect of electrolyte and membrane potential.
15. Using coarse grained models studying the protein stability, extending the model to include membranes, electrolytes and electrodes, as well as voltage‐activated proteins, protein insertion through the translocon, and the action of molecular motors.