Solvent-protein interactions simulations

To date, a number of simulation studies have been performed on nucleic acids and proteins using both AMBER and CHARMM. A direct comparison of crystal simulations of bovine pancreatic trypsin inliibitor show that the two force fields behave similarly, although differences in solvent-protein interactions are evident [24]. Side-by-side tests have also been performed on a DNA duplex, showing both force fields to be in reasonable agreement with experiment although significant, and different, problems were evident in both cases [25]. It should be noted that as of the writing of this chapter revised versions of both the AMBER and CHARMM nucleic acid force fields had become available. Several simulations of membranes have been performed with the CHARMM force field for both saturated [26] and unsaturated [27] lipids. The availability of both protein and nucleic acid parameters in AMBER and CHARMM allows for protein-nucleic acid complexes to be studied with both force fields (see Chapter 20), whereas protein-lipid (see Chapter 21) and DNA-lipid simulations can also be performed with CHARMM. 

The simulation results presented in this section illustrate two essential features of the solvent and of solvent-protein interactions which influence protein dynamics. One is concerned with the spatial coupling (i.e., the degree of coupling between solvent and protein, which is related to solvent accessibility or some other measure of direct relatively short-range solvent-protein interactions), and the second is concerned with the time-scale coupling (i.e., the degree to which the motions of the solvent are commensurate with the temporal... 

Proper condensed phase simulations require that the non-bond interactions between different portions of the system under study be properly balanced. In biomolecular simulations this balance must occur between the solvent-solvent (e.g., water-water), solvent-solute (e.g., water-protein), and solute-solute (e.g., protein intramolecular) interactions [18,21]. Having such a balance is essential for proper partitioning of molecules or parts of molecules in different environments. For example, if the solvent-solute interaction of a glutamine side chain were overestimated, there would be a tendency for the side chain to move into and interact with the solvent. The first step in obtaining this balance is the treatment of the solvent-solvent interactions. The majority of biomolecular simulations are performed using the TIP3P [81] and SPC/E [82] water models. 

Most protein folding simulations using explicit solvent consist of 80 or more percent water, and it turns out that the calculation of the water interaction indeed also takes more than 80% of the CPU time. Some MD packages improve on this by using a special routine for the water interaction [42]. Nevertheless, it seems a waste that most of the computer time is spent on solvent molecules... 

Application to the BPTI Crystal. The system to be simulated consisted of the protein atoms of one BPTI molecule (5) and 140 water molecules. The required number of water molecules could be calculated both from the volume of the crystal for which protein-water energy is zero or negative (solvent space) (9) and from unit cell volume and density of protein and water. Protein-water interactions were calculated as in the first part of this article, protein-protein interactions as described elsewhere ( ). Interactions between water molecules were calculated using the ST2 model, introduced by Rahman and Stillinger in a molecular dynamics simulation of liquid water (11). 

A simulation of solutes and solvent molecules interacting and an animation of osmotic flow between two flexible compartments are located here http //phvsioweb.med.uvm.edu/bodvfluids/osmosis.htm. A simulation of the osmotic pressure experiment above for NaCI, sucrose, and albumin (a protein) is found here ... 

For complex calculations, use no cutoff for nonbonded interactions between ligand and protein, and ligand and solvent, and a residue-based cutoff of 15 A between solvent and solvent, protein and protein, and protein and solvent freeze all protein residues outside the solvated region. Choose either the FEP or TI method for calculating relative free energies. Prior to the simulation, use 2000 steps to energy minimize both solvated and complexed states. 

---