Objective and Overview

The objective of this tutorial is to familiarize users with the Merck Molecular Force Field (MMFF) in CHARMM along with the use of the interaction energy command. The system being studied is the protein glycogen phosphorylase with the bound inhibitor CBP (PDB identifier 1c8k). In addition, two water molecules that are thought to be important for binding are included. Images of the structure are below. The needed coordinate files are: 1c8k_cgen.crd, tp3m_36_98.crd, and cpbh.mol2

In the input file, mmff_inter_energy.inp, the MMFF force field is first setup. As MMFF is a Class II force field it requires significantly more input than the standard CHARMM force fields. The necessary files are in the toppar and toppar/data subdirectories. Once MMFF is setup the inhibitor, protein and two waters are read and the respective structures generated. This is followed by calculation of the interaction energy between 1) the drug and the protein and 2) the drug/water complex and the protein. This is first done using the crystal structure directly, followed by the minimization of the two waters with the drug and protein constrained. Additional interaction energy commands are performed following minimization of the drug and water with the protein fixed and of the drug, water and the local protein environment minimized. The resulting interactions energy are output in the file 1c8k_cpbh_1.inter for analysis.

When using the INTERaction energy command it is important that the nonbond lists be setup properly. This requires a call the ENERgy prior to the INTERaction command. Importantly, when using the CONS FIX command for the minimization it is essential to remove the constraints (CONS FIX sele none end) then perform an ENERgy command prior to the INTERaction command. This is necessary due to the CONS FIX command altering the nonbond list in order to save computer time. Finally, the INTERaction energy command may be used with the standard CHARMM force fields in the same way as with MMFF.