Method

Method

Potential used :

A mixed-resolution potential is used for the simulations, in which majority of the protein is treated with a Go model and the atomistic region around the binding site is treated using the AMBER force field.
-The overall potential takes the following form:

-U = U_CG + U_AA + U_CG/AA + U_SEDDD

Here -

U_AA The all-atom potential U_AA is the potential energy of the all-atom region, according to the AMBER 99SB force field.

U_CG/AA : U_CG/AA describes the interaction energy between the particles in the all-atom region and the coarse- grain region and they are computed atomistically using the AMBER99SB force field. As mentioned above, each amino acid in the coarse-grain region is rigid and moves along with its corresponding Cα. (The energies are included in the same term with the interactions between atoms in the all-atom region.)

U_bb : U_bb is the backbone potential in the coarse-grain region. The code uses the bond/angle/dihedral parameters from the all-atom force field for backbone atoms (N, Cα, C) to hold the protein together. The Go potential is a residue level potential defined between Cα carbon positions, so i and j, represent residues not in the all-atom region, and r _ij is the distance between the Cα of residue i and that of residue j. (Each amino acid in the coarse-grain region is treated as a rigid body.)

U_SEDDD : U_SEDDD is the solvent-exposure and distance dependent dielectric function following the work of Garden and Zhorov (J.Comput.AidedMol.Des, 2010, 24:91-95). The MRMC code uses rules to determine which atomistic interactions need to be recomputed as part of the calculation of ∆U for each trial move. One of these rules is that, if the change in the fractional solvation volume v _k as a result of a move is greater than the tolerance specified, then any interactions involving that atom will be recomputed. The recommended value ensures that this rule selects enough interactions to give accurate values of ∆U while possibly avoiding some computer time recomputing interactions that do not need to be computed.

Ligand Topology :

The ligands have to be all-atom. Their topologies are defined in the definitions file. Scripts for pro- ducing these can be found in the ”par-scripts” directory. Ligands are parameterized with the antechamber tool using the GAFF force field.

In order to incorporate solvation effects in a computationally efficient manner, the electrostatic term of the AMBER 99SB was modified to use a solvent-exposure dependent distance dependent dielectric originally developed by Garden and Zhorov [Garden2010].