protoms ELBAlipids gcmc replica_exchange digital_filtering


Computer simulations of molecular systems are a vital component of modern chemistry and physics. They are being used, for example, in such diverse areas of research as the fundamental physics of crystal nucleation, through to the design of new pharmaceutical entities. Research in the Essex group focuses on innovation in the application of computer simulations to biological systems, where there is the potential to contribute to drug discovery and the development of medical diagnostics. A key challenge restricting success has been limitations in the range of applicability of these computational methods, and in the extent to which accurate predictions may be made. To address these issues, a cross-disciplinary approach that develops new methodologies and deploys these over more realistic systems is used.

Protein systems

Docking prediction
Docking prediction

The work of the group on proteins can be divided into the following fields:

Protein-ligand interactions are critical in determining the effectiveness of pharmaceutical compounds, and computer simulations are ideally suited to probing these interactions. There are essentially two problems to be solved: First, is it possible to predict the structure of a protein-ligand complex given the protein structure, and second, can the binding free energy of the resulting complex be accurately calculated? If these objectives can be met, then the reliable use of structure to predict novel pharmaceutical compounds will become a reality.

Past work involved the developement of structure prediction algorithms that incorporate receptor flexibility. This method is currently undergoing further testing and validation. The role of water molecules present in a protein ligand binding site is the subject of much debate and developing computational methods that consider their role in ligand design is a challenging task. The binding free energy of these water molecules can be calculated by application of the formalism of statistical thermodynamics. Using this approach, we have been able to discriminate between water molecules that can be displaced by ligands and those that are more tightly bound. Indeed, we have shown that the effect of ligand binding on trapped water molecules can make a very significant contribution to the overall protein-ligand binding affinity.

Reliable binding free energy calculations requires extensive sampling of the range of possible ligand-protein interactions to yield meaningful results. Protocols that combine Replica Exchange methodology (used extensively in molecular dynamics simulation of protein conformational changes) and free energy calculations have been developed in the past. Current work considers non equilibrium methods, novel Monte Carlo moves and approximate methods of solvation to improve the efficiency of these computations.

Group members working in this field :

Biological membranes

Gay Berne model of a membrane
Gay Berne model of a membrane

The work of the group on membranes can be divided into the following fields:

Routine computer simulations of biological systems have, until recently, been limited to at most 100 000 atoms. This is sufficient to study a single large protein in an aqueous environment. However, real biological systems are substantially larger than this, and if simulation is ever to offer insight into how, for example, lipids and proteins interact in a fully functioning cell membrane, approaches to simplify the atomic representation and increase the granularity of our models are needed.

Past work has focused on atomistic simulations of small molecule and drug permeation through model membranes. These simulations have provided insights in understanding how readily drugs reach their target. Simplified molecular models have long been used in the area of modelling liquid crystal systems, with considerable success. A simplified model of the membrane environment, based on the Gay-Berne model of liquid crystals has been developed. In addition, we have combined this model wtih atomistic representations of small molecules, in a dual-resolution approach, allowing for the effect of small molecules and drugs on membrane stability to be simulated efficiently and directly.

Future work will likely focus on coarse-grained models of protein and DNA, and extensions of the dual-resolution methodology to larger systems. These studies will address not only the fundamental physics needed to develop successful coarse-grained models, but will also attack important biological problems such as protein-mediated membrane fusion.

Group members working in this field :

School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ.