Modulation of PDZ Domain Binding by ps-ns Side-chain Dynamics.

摘要

Typical of protein-protein interactions, PDZ domain binding is driven by a complex array of forces with unclear molecular determinants for ligand recognition. We hypothesize that many of the most complex aspects of PDZ domain-driven protein-protein interfaces are determined, in part, by the mobilities of sidechains. We make a case for dynamics as an essential basis for PDZ domain promiscuity, PDZ domain specificity, and PDZ domain allostery. In doing so, we make significant progress in defining the relationship between dynamics, structure, and function.;Analogous to sequence homology studies, this investigation attempts to reveal the connection between dynamics and function by studying the dynamics homology within a set of evolutionarily linked proteins. We demonstrate that the global pattern of flexibility and rigidity is conserved within the PDZ domain family which suggests an evolutionary pressure to selectively fine tune the fast dynamics of side-chains. This conservation is proven not to be a trivial re-capitulation of structural or sequence conservation. Also, the degree of conservation of the global dynamic character, or dynamics motif, of PDZ domains can be used to segregate PDZ domains into functionally relevant subfamilies. Conservation of local, or site-specific, dynamics has functional applications as well. Interestingly, we are able to identify functionally important residues distal to the binding pocket based solely on dynamics conservation.;Finally, we describe a mechanism for dynamics-driven allostery. In the third PDZ domain of PSD95, allostery is propagated by the interplay of changes in side-chain dynamics and changes in the protein's volume. Surprisingly, these changes occur in the context of no observable structural change.