The importance of slow motions for protein functional loops

Abstract

Loops in proteins connect secondary structures such as alpha-helix and beta-sheet, are often on the surface, and may play a critical role in some functions of a protein. The mobility of loops is central for the motional freedom and flexibility requirements of active-site loops and may play a critical role for some functions. The structures and behaviors of loops have not been much studied in the context of the whole structure and its overall motions, and especially how these might be coupled. Here we investigate loop motions by using coarse-grained structures (Cα atoms only) to solve for the motions of the system by applying Lagrange equations with elastic network models to learn about which loops move in an independent fashion and which move in coordination with domain motions, faster and slower, respectively. The normal modes of the system are calculated using eigen-decomposition of the stiffness matrix. The contribution of individual modes and groups of modes are investigated for their effects on all residues in each loop by using Fourier analyses. Our results indicate overall that the motions of functional sets of loops behave in similar ways as the whole structure. But, overall only a relatively few loops move in coordination with the dominant slow modes of motion, and that these are often closely related to function.

How an Inhibitor Bound to Subunit Interface Alters Triosephosphate Isomerase Dynamics

“…NMR studies have suggested that loop 6 motion is partially rate limiting in the interconversion between DHAP and GAP (13). Previous computational studies, including both coarse-grained elastic network modeling (ENM) and classical MD simulations (9,10,(14)(15)(16)(17), have indicated that the loop dynamics are coupled with the global modes of TIM, which can be identified as counterrotation and bending of subunits. Similar coupling has been observed in other enzymes with functional loops (17), suggesting that the global modes of such enzymes enable or facilitate the functional loop motions.…”

Substrate Effect on Catalytic Loop and Global Dynamics of Triosephosphate Isomerase

“…More recently, several studies have appeared that emphasize such coupling between energetically-favored global modes of motion and functional loop dynamics [10][11][12] for a larger set of proteins. Specifically, for a set of 10 enzymes with different sizes and oligomerization states, it has been shown through ENM that the experimentally determined catalytic loop (10-20 residue-long) reconfigurations are driven, at least to a certain extent, by collective modes of the intact enzyme in the apo state [10].…”

Dynamics of βB2-Crystallin Motion Based on Principal Component Analysis and Normal Mode Analysis

“…However, the cataract pathology was unlikely to be associated with a direct folding defect [47]. Collective motions suggest that flexibility and internal motions are important for many protein functions [48][49][50]. Principal component analysis (PCA) and normal mode analysis (NMA) are invaluable tools for studying conformational changes in proteins.…”