Dynamics of Protein–Ligand Interactions

Introduction

Proteins are biological macromolecules that are vital to all processes of life. Understanding the functions of proteins has great scientific and commercial value: proteins are used as industrial enzymes, as pharmaceutical treatments, and many proteins are the targets of drugs.

Current Knowledge and Limitations

Current knowledge of protein function is primarily based on static structures, which have provided great insights about structure-function relationships that today form the basis for protein science and protein engineering.

Proteins are, however, not static molecules, but undergo spontaneous transitions between alternative structural states, some of which are rare, transient conformations that are essentially invisible to traditional methods. These dynamical properties are known to be critically important for function, but high-resolution studies of dynamics have so far been conducted merely as an add-on following structural studies.

Project Goals

To change the situation, we aim to establish integrative biomolecular dynamics by developing methods that integrate:

1. Time-resolved X-ray crystallography
2. Nuclear magnetic resonance spectroscopy
3. Molecular simulations

This will allow us to study the motions of proteins while they carry out their function.

Focus Area

We focus on the challenging problem of molecular recognition because it represents a poorly understood frontier in molecular science where advances are expected to have great impact. Specifically, we will address the question of how proteins bind ligands by describing with atomic resolution the entire dynamic process to reach a consistent kinetic, thermodynamic, and structural view.

Method Development

We are at a point where it will be possible to develop the individual techniques required for our integrative biomolecular dynamics approach. As a team, we can leverage ongoing developments in hardware and methods, while ensuring the tight integration between methods that is needed to study complex dynamical systems.

Conclusion

We thus aim to move structural biology into a new era of protein dynamics.