Analyzing protein active sites using the XED force field

Analyzing protein active sites using the XED force field was presented by Dr Mark Mackey, Cresset at the Cresset European User Group Meeting 2015.

Mark presented recent work carried out by Cresset’s scientist on applying the XED force field to protein active sites. The basic question was, can we apply fields to proteins? Mark presented work on water mapping and on modeling the electrostatics around the ligand.

Electrostatic mapping of protein active sites

Cresset’s electrostatic model is more detailed than other MM based approaches. Understanding the subtleties of the protein active sites should help inform ligand design. However, the sorts of methods that work well in small molecules don’t necessarily scale to large molecules. Some of this is a question of computational power. Some of this is to do with the quality of input data from the proteins.

When carrying out computational work on proteins there is a lot of preparation work required. You need to know which way the hydrogens are pointing and you also need to know what is happening in terms of solvation effects. The work resulted in good electrostatic maps of the protein interactive site. Mark gave several examples of electrostatic maps and went through the details of the interactions at different areas of the sites.

Mark concluded that there is still some research about how to do the displays. If you try to condense them down to field points for proteins, they are not so easy to interpret. Surfaces are much easier to interpret.

Water mapping

The team also carried out water analysis on full sized proteins to determine the water position and thermodynamics. They used 3D-RISM to determine where the water is and how happy it is. They concluded that the results are only as good as your potential functions. The next question was, does the XED description of electrostatics improve the results?

They found that XED provides better short-range electrostatics. Mark illustrated this with an example whereby the XED force field method shows correct water placements around small molecules such as acetone, while the Amber results are incorrect. This technique has been extended to full size proteins to determine where the water wants to go and what the thermodynamics of the water are.

Two examples were given – comparing the Amber and the XED force fields. It was found that the Amber and XED force fields tend to agree on water position, but not degree of stability.

Combining electrostatics and water mapping

The stable water in an active site is potentially difficult or costly to displace, so it makes sense to treat it as part of the active site. The electrostatic map of the active site including the stable waters can differ substantially from the dry active site. The combination of using the RISM based water mapping technique in conjunction with computing electrostatic field potentials is a great way of working out what you want to keep about your compounds and what you want to change.