Local Flexibility in Molecular Function Paradigm

Abstract

It is generally accepted that the functional activity of biological macromolecules requires tightly packed three-dimensional structures. Recent theoretical and experimental evidence indicates, however, the importance of molecular flexibility for the proper functioning of some proteins. We examined high resolution structures of proteins in various functional categories with respect to the secondary structure assessment. The latter was considered as a characteristic of the inherent flexibility of a polypeptide chain. We found that the proteins in functionally competent conformational states might be comprised of 20 -70% flexible residues. For instance, proteins involved in gene regulation, e.g. transcription factors, are on average largely disordered molecules with over 60% of amino acids residing in "coiled" configurations. In contrast, oxygen transporters constitute a class of relatively rigid molecules with only 30% of residues being locally flexible.

Sampling Conformation Space to Model Equilibrium Fluctuations in Proteins

“…There is no evidence of any correlation between global physico-chemical properties such as stability or contact order [17] and the nature, local or correlated, of protein fluctuations. Moreover, despite the limited information on protein structures and motions available in current databases [18] and literature, proteins with non-concerted motions represent a significant portion of proteins with known structure [19], [20]. For the proteins studied in this article, our results show that PEM-modeled fluctuations are fully consistent with multiple timescale measurements obtained from NMR wet-lab experiments and guided simulation techniques.…”

“…The results presented in Section 5 indicate that PEM allows us to model with remarkable accuracy equilibrium fluctuations in proteins with non-concerted motions. The applicability of PEM to such proteins is important because proteins with non-concerted motions represent a significant fraction of proteins with known structure [19], [20]. Moreover, the comparison of PEM-modeled fluctuations with experimental data can be used as a framework to test whether local fluctuations are sufficient to explain experimental data.…”

Asparagine of z8 Insert Is Critical for the Affinity, Conformation, and Acetylcholine Receptor-clustering Activity of Neural Agrin

“…In addition, our study also provides insight into how locally flexible, intrinsically unstructured domains contribute to protein function and signaling. These domains comprise a significant portion of the proteome, yet their importance has only recently been appreciated (44,45).…”

An androgen receptor N-terminal domain antagonist for treating prostate cancer

“…The plasticity of IDPs with labile regions that can be shaped by their environment and interactions provides potential for small-molecule binding (33). However, the general property of reversible, low-affinity binding of IDPs to many interacting partners to facilitate the exchange of binding partners may forecast a requirement of irreversible binding for any small-molecule inhibitor to have a sustained therapeutic effect.…”