Calibrating the GRID Force Field

It is often convenient to think of drugs and proteins in terms of their chemical formulae and three-dimensional structures. However, an alternative interpretation is to regard the structure as nothing more than a set of frictionless rods and levers which transmit forces from one part of the system to another. This is the philosophy which underlies GRID, and it puts the main emphasis onto thermodynamics rather than structure. However it does raise a number of problems  

When the thermodynamic viewpoint has been adopted, it is the free energy of the system rather than the chemical structure of the molecules which needs the most careful study. Free energies can be most conveniently computed for reversible equilibria, and so the results from GRID should apply, strictly speaking, only to equilibrium systems. GRID has been found in practice to give useful predictions [8-11], but it is not easy to estimate the size of any errors caused by deviations from equilibrium. 

One of the earliest decisions was to calibrate the GRID force field whenever possible by using experimental measurements rather than theoretical computations, and calorimetric measurements were therefore needed for the initial calibration in order to differentiate the enthalpic and entropic contributions to the overall free energy. However, only a very little calorimetric data was readily available at that time, about well characterised biological systems in which the structures of the interacting ligand and macromolecule were both known, and so a different approach was initially needed. 

All the necessary data was collected together in a file called GRUB which is revised whenever a new version of the program GRID is released. The first part of the GRUB file contains data values for ATOMS in known molecules (The natural amino acids, heme, cofactors, etc.). For example, there is an entry for the NZ ATOM of lysine. The second part of GRUB has individual HETATM values, and so it has an entry for N3-I-. 

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