A calorimeter at atomic resolution

Introduction

Molecular interactions are at the basis of all biological processes and often include specific interactions between macromolecules (protein, RNA, DNA) and small-molecule ligands, such as cofactors, hormones, drugs, or metabolites. Detailed and quantitative knowledge of these interactions is critical for a molecular understanding of these biological processes and developing new therapeutic solutions.

Importance of Molecular Recognition

A complete comprehension of molecular recognition requires a full characterization of the geometry and dynamics of the molecular complex. This includes not only the internal dynamics of each partner but also the dynamics at the interface, which to date remain mostly unexplored experimentally.

Thermodynamics of Molecular Interactions

The physical chemistry frame for studying intra- and inter-molecular interactions is thermodynamics. The extent to which two molecules interact is dictated by the Gibbs energy change (ΔG) of the interactions, which is composed of:

1. Enthalpic (ΔH) terms
2. Entropic (ΔS) terms

X-ray crystallographic and NMR structures provide a detailed description of the static interactions associated with enthalpic contributions. However, up to now, the entropic components remain difficult to address experimentally.

Project Goal

The overarching goal of this proposal is to develop a calorimeter at atomic resolution. To achieve that goal, a new NMR spectroscopy approach, relying mainly on the nuclear Overhauser effect, will be developed.

Anticipated Outcomes

It is anticipated that quantitative thermodynamic measurements within molecules and molecular complexes will open a new avenue in the fundamental understanding of how atomistic mechanism(s) create a function.

Applications

Beyond the fundamental findings, we foresee applications in:

• Translational medicine
• Drug design
• Computer-assisted molecular design