Scientific Background

This workshop concerns simulation of the behaviour of biological macromolecules and their interactions at the atomistic level using first principles quantum mechanical techniques.

The application of ab initio modelling across diverse fields such as condensed matter physics, materials science and chemistry has been demonstrated over the past 10 years. It has become clear that high quality simulations require a proper quantum mechanical treatment of the bonding and other interatomic forces, and techniques for achieving this are well established [1]. However, it is only recently that computational techniques have provided the means to directly solve the quantum mechanical equations for systems of sufficient complexity to provide useful information in a biological context.

The recent completion of the Human Genome Project will offer an unprecedented number of protein receptors and enzymes as targets for pharmacological intervention in disease processes. However, before this wealth of information can be used to develop pharmaceuticals, an understanding of the biochemistry of the newly identified proteins and their interactions must be obtained. First principles quantum mechanical modelling will play an important role in this process.

The utility of first principles modelling in biological fields has been demonstrated in a number of recent applications. These include:

• The application of first principles calculations to the cytochrome P450 superfamily of enzymes by Dr M. D. Segall (see for example refs. [2,3,4]). Drs Harris and Loew at the Molecular Research Institute in the U.S.A. [5] and Dr M. J. de Groot, currently at Pfizer Central Research, U.K. [6], have also studied this system using ab initio methods;
• An investigation of the copper enzyme galactose oxidase and related biomimetic compounds by Prof. U. Rothlisberger of ETH, Zurich, Switzerland [7];
• A study of HIV-1 protease, a promising target for treatment of AIDS, by Drs S. Piana and P. Carloni, of SISSA, Trieste, Italy [8]; and
• Modelling of the chromophore of rhodopsin, a protein responsible for detection of light in the retina, by Dr C. Molteni, currently of the University of Cambridge, in collaboration with Dr I. Frank and Prof. M. Parrinello of the Max-Planck-Institut für Festkörperforschung, Germany [9].

It is important to achieve a mutual understanding, between scientists applying ab initio modelling and those working in the biological sciences, of the capabilities of ab initio modelling and the important biological problems to which they may be applied.