Cresset’s main focus is the description of molecules in terms of electrostatics. For this to be effective, the electrostatic model needs to be accurate. Quantum mechanics calculations can give very accurate electrostatic potentials, but are still too slow in most cases. As a result, an accurate method of computing electrostatic potentials in a molecular mechanics context is needed.
Most standard force fields use the atom-centred charge (ACC) approximation: the electrostatics of the molecule are approximated by a set of point partial charges placed on the nuclei. Many methods are available to compute these partial charges (Gasteiger-Hückel, AM1-BCC, etc), but the underlying model is one point charge per atom. This method can work well for the gross long-distance electrostatic potential (e.g., dipole moments), but performs poorly when describing the electrostatic potential near the molecular surface. This is because atoms are not charged spheres: they have lone pairs, pi orbitals, sigma holes and so forth. In addition, atoms and molecules are polarizable and change their electrostatic behavior in response to external electric fields. The ACC model covers none of these effects. Newer force fields such as AMOEBA solve this problem by placing explicit multipoles and polarization functions on the atoms, which does give a much more realistic electrostatic potential. These force fields perform well on proteins but have issues with parameter transferability which makes them largely unsuitable for ligand modeling.
The XED force field was the first major effort to solve these electrostatic problems, and did so not by placing explicit multipoles on atoms but by placing additional monopoles around them. The technique was originally introduced by Hunter and Sanders, JACS 1989, to model aromatic-aromatic interactions, and was extended into a full general-purpose force field by Cresset’s founder Andy Vinter, JCAMD, 1994.
Additional monopole points, or XEDs (eXtended Electron Distributions), are treated within the force field as atoms with zero van der Waals radii. They are not placed in a rigid geometry with respect to their parent atom. Instead, they come with bond stretching and angle bending potentials and can move under the influence of external (and intramolecular) electrostatic potentials, allowing the direct modeling of polarizability. The more complex internal electrostatic model allows for intramolecular electrostatic/orbital interactions such as the anomeric effect to be modeled without the introduction of specific torsional parameters: the anomeric effect falls naturally out of the electrostatic model and does not need to be added post hoc.
The XED force field has been demonstrated to provide quantitatively superior results for the energetics of aromatic-aromatic interactions. Cresset’s academic collaborators have used the XED model to study and predict specific intermolecular interactions. For example, Professor Chris Hunter studied the dimerization of a series of di-aryl amides using NMR and computational chemistry (Substituent Effects on Aromatic Stacking Interactions). He found that the XED model accurately predicted the experimentally observed association constants.
The superior modeling of aromatic interactions was used to design aromatic ‘zippers’ for linking collagen mimic fibres (Thrombogenic Collagen-Mimetic Peptides: Self-Assembly of Triple Helix-Based Fibrils Driven by Hydrophobic Interactions).
Over the last 20 years the XED force field has undergone numerous improvements. Unlike most other force fields, the XED force field is parameterised where possible against experimental data (microwave conformation energies, small molecule crystal structures etc.) rather than relying purely on ab initio calculations. XED 3, released in 2012 offers an improved treatment of nitrogen, amongst many other enhancements. Rather than having to assign separate types for trigonal and tetrahedral nitrogen, the XED 3 force field determines on the fly the degree of pyramidalization that is appropriate in any given molecular environment, allowing for a continuum from completely flat N to completely pyramidal N. In addition, XED 3 has an improved description of halogens, correctly describing the ‘sigma hole’ in the heavier halogens and giving good results for halogen bonding. Cresset continues to develop and improve the force field on an ongoing basis.
