The Two Faces of Protein Flexibility: A Topological Approach

Conclusion: This stems from the large amount of observations pointing to natively unfolded tracts of protein sequences as responsible for protein-protein interactions. Given the interaction with other macromolecules is the core of protein physiological role, in a local (orthosteric) paradigm of pharmacological action, we maximize the probability of perturbing the system by an agent binding in the same place where such interaction takes place: the most flexible parts of the structure. In the case of an allosteric (non-local) paradigm, the focus shifts toward the signal transmission across the protein molecule: this renders the ‘most promising’ binding sites those residues with the most ‘central’ position that have the higher probability, when perturbed by a ligand, to generalize the perturbation to the entire structure. Protein contact network (PCN) formalism allows for a rational, structure based approach to both the drug action modes.
Source: Current Chemical Biology - Category: Biochemistry Source Type: research