CECAM Workshop on

Calculation of
concerted motions in biomolecules
October 11-14, 1999





Wendy Cornell
Novartis Pharmaceuticals, USA

Michael Nilges
EMBL, Heidelberg, Germany

Roger Abseher
EMBL, Heidelberg, Germany



CECAM
Ecole Normale Superieure de Lyon,
46, Allee d'Italie,
69364 Lyon CEDEX 07 - FRANCE



Additional sponsors:
Novartis Pharmaceuticals
SGI
Pharmacia-Upjohn
Pfizer


Scientific Background
    For over forty years, structural biology has provided important insights into the mechanisms of biological molecules. The determination of the structure of DNA in 1953 by Watson and Crick and of hemoglobin and myoglobin in the late 1950's by Perutz and Kendrew opened up an era where biological function could be studied at the atomic level. Nevertheless, for the most part, this information provided by X-ray crystallography and NMR spectroscopy has been in the form of a static picture (or pictures) of these molecules. It has long been recognized, however, that proteins are dynamic plastic entities, not only capable of motion, but, indeed, often required to deform in order to carry out their biological functions. These motions may be local, in the form of sidechain rotamer changes or segmental movement of secondary structure, or global, in the form of hinge bending or inter-domain motion.

    Normal mode, essential dynamics, and principal component analysis are all techniques for defining the dynamic properties of molecules in a concise and compact manner. A mode based model can be derived either ab initio from the harmonic approximation or by a post-facto analysis of a molecular dynamics trajectory. Normal mode calculations have been used to calculate the contribution of vibrational entropy to the dimerization of insulin, the contribution of cross-links to the stability of bovine pancreatic trypsin inhibitor, and the binding of peptide ligands to Src-SH2 domains. They have also been used to investigate hinge bending in lysozyme and CD4, the human receptor which binds to the gp120 envelope protein of HIV. Normal mode calculations have been incorporated into the refinement schemes for x-ray and NMR data in order to define a "dynamic structure" which would give rise to the observed data. They have also been applied to the field of conformational searching, allowing the search to proceed along the natural modes of distortion of the molecule and resulting in a technique which is outperforming other techniques based on stochastic or molecular dynamics approaches. All of these applications clearly underscore the importance of a dynamic model for understanding molecular function.

    Current interest in concerted motions is also evident from the number of papers published recently in structural journals which focus on both small and large scale conformational changes. Such changes are more readily observed experimentally as the number of structures solved for a given system increases. Theoretical techniques for simulating such concerted motions have been shown to reproduce this experimental data. Finally, the theoretical techniques provide the advantage of including structural and energetic information within one model.



Motivation and objectives
    Normal mode, essential dynamics, and principal component analysis are all techniques for investigating the dynamic properties of molecules. These types of analyses differ from straight molecular dynamics approaches in that they provide a concise and compact description of the concerted motions of the molecules. These techniques have a variety of applications, among them: investigation of induced fit in ligand binding, calculation of molecular vibrational entropy, definition of quaternary motions in multi-domain proteins, refinement of x-ray and NMR structural and dynamic data, and conformational searching. This has become an increasingly active area of research over the past eight years and a workshop which would bring together researchers from the field would be quite timely. The rapid and overwhelmingly enthusiastic response of the potential workshop participants demonstrates the need for such a workshop.

    The general objective will be to bring together theoreticians and computationally oriented experimentalists in order to foster a cross-pollination of ideas regarding the calculation and application of concerted motions to problems of biological interest.



To get more information contact: Wendy Cornell