Conservation of Side-Chain Dynamics Within a Protein Family

The question of protein dynamics and its relevance to function is currently a topic of great interest. Proteins are particularly dynamic at the side-chain level on the timescale of picoseconds to nanoseconds. Here, we present a comparison of NMR-monitored side-chain motion between three PDZ domains of ∼30% sequence identity and show that the side-chain dynamics display non-trivial conservation. Methyl 2H relaxation was carried out to determine side-chain order parameters (S2), which were found to be more similar than naively expected from sequence, local packing, or a combination of the two. Thus, the dynamics of a rather distant homolog appears to be an excellent predictor of a protein's side-chain dynamics, and, on average, better than current structure-based methods. Fast side-chain dynamics therefore display a high level of organization associated with global fold. Beyond simple conservation, the analysis herein suggests that the pattern of side-chain flexibility has significant contributions from non-local elements of the PDZ fold, such as correlated motions, and that the conserved dynamics may directly support function