The Strength of Weak Affinity Interactions
Sten Ohlson, School of Biological Sciences, Nanyang Technological University, Singapore
Weak or transient biological interactions with affinities of Kd > μM, either working alone or in concert, play an important role in sustaining a biological system and we are only recently starting to realize their importance in a range of complex biological networks. Due to the difficulties to see them (“how to see a similar tree in the forest”) and the fact that many non-specific interactions are of a transient nature have made them notoriously hard to study and they have been considered as essentially of no value.
In my ISMR award lecture, I will attempt to convince you that weak/transient biological interactions can be measured with a number of techniques including affinity chromatography, capillary affinity electrophoresis, surface plasmon resonance and fluorescence techniques. I will highlight the work we have done through the years in weak affinity chromatography (WAC) where transient binding between a receptor and ligand forms the basis for separation and analysis. Of special importance has been the introduction of weak affinity based HPLC/MS based approaches for applications in drug discovery and clinical diagnostics. Examples will be demonstrated on fragment screening for drug development and steroid analysis in clinical chemistry.
Furthermore, the dynamic nature of a transient interactions can be of great value in a number of areas. The development of continuous biosensors have been realized by weak binding between the target analyte and a suitable receptor. Examples will be given on carbohydrate sensing including continuous monitoring of glucose for diabetes control. Maybe the most interesting aspects of the realization of the importance of transient interactions among biomolecules is the challenge of the current paradigm of drug design to find the tightest binder (with affinity typically in the nM range) to a given drug target (“the magic bullet approach”). I postulate that a transient binding drug, if properly designed, can be an alternative successful approach to drug discovery. Of special importance is the hypothesis that the success of polypharmacologic drugs (“the magic shotgun approach”) is dependent on the design of weaker binders. I will discuss this in more in detail in my presentation and give some highlights of our work on developing transient polybinders to cancer targets and as antibiotic agents.
Even though it is challenging to study weak interactions, tools are now available in affinity technology to study these subtle molecular events. I am convinced that if you suspect of having weak binding events in your research, it can be properly studied and explored favourably.