Modulation of protein-protein interactions for the development of effective therapeutics - from a joint perspective of experiment and computation

Abstract

Many proteins present in living organisms act as obligate oligomers – that is to say - they require other protein partners to function properly. Oligomerization does not only lead to the formation of physical interactions, which are required to hold individual protomers together in these assemblies, but it also triggers the cross-talk within the oligomer, so that individual protomers can regulate and modulate each other’s function in the form of either inhibition or activation. Consequently, this notion has changed the classical “single-target” pharmacology to “multi-target” one, urging the development of novel approaches in the field of drug discovery. In general, modulation of the function of a particular complex can be done by means of small-molecules developed specifically to target the interface between the protomers. This requires atomistic-level knowledge regarding the structure and dynamics of the system. As such, numerous experimental techniques were established in order to identify the partners in these assemblies. However, data solely based on these experimental techniques do not provide a mechanistic insight on the system as it cannot provide atomistic-level information per se regarding inherent allosteric interactions that govern the function of the complex. In this respect, computational methods act as indispensable tools to complement and to provide careful experimental data interpretation. The combination of these two worlds paves the way to the development of new, efficient and specific therapeutics.