FORCE FIELD PARAMETERS FOR CHARGED GROUPS IN CONDENSE PHASE 

 

- Structures and free energies of biomolecules are mainly determined by electrostatic interactions.

- These are in particular between charged groups.

- Relative free energies (of hydration) can have errors > 10 kcal/mol per charged group.

- No force field consistently describes e.g. the relative free energies of charged side chains.

- This is the major reason for the failure of many current protein simulations.

- Thus, we are optimizing new force field parameters for charged amino acids and ions.

BECAUSE OF THEIR DIFFERENT PROPERTIES, EACH WATER MODEL REQUIRES SEPARATE FORCE FIELD PARAMETERS TO MODEL FREE ENERGIES OF HYDRATION CORRECTLY.

As an example, the difference in free energy of hydration of a charged group can differ by more than 10 kcal/mol when computed in TIP4P or TIP3P water.

- We work mainly with TIP4P but have parameterized protein parameters for TIP3P / SPC as well.

FIGURE 1. A salt bridge illustrates the problem of obtaining proper force field parameters for charged residues, due to long-range electrostatic effects and the critical importance of the free energy of hydration.

To illustrate the problem, the free energy of a salt bridge is given by the free energy of the paired amino acids minus the hydrated amino acids (see Figure 1, on the right).

Protein folding is for example mainly described by the total dehydration free energy of charged residues forming salt bridges and other interactions within the native protein.

When any charged amino acid in a protein changes environment, e.g. upon ligand binding or protein-protein interactions, it will change its free energy relative to other charged groups.

It is thus exceedingly important to put all charged amino acids on the same free energy scale.

The treatment of long-range electrostatics is the crucial aspect of this problem. To put anions and cations on the same free-energy scale, full account of the electrostatic interactions is necessary.

For any ion in water, the water-water interactions are unfavorable as they align water molecules towards the ion. The ion-water interactions compensate this interaction and are always favorable.

A spherical model with constraints worked well for including all interactions within a given radius, and was shown to be size-consistent beyond a radius of 10 Å, incl. Born correction, Figure 2, left. This model thus gives converged  free energies of charged species and was used.

 K. P. Jensen, W. L. Jorgensen, "Halide, Ammonium, and Alkali Metal Ion Parameters for Modeling Aqueous Solutions",

 J. Chem. Theory. Comput. 2006, 2, 1499-1509.

 

 K. P. Jensen, "Improved Interaction Potentials for Charged Residues in Proteins",

 J. Phys. Chem. B 2008, 112, 1820-1827.