Molecular Dynamics Study of Naturally Existing Cavity Couplings in Proteins

Abstract

Couplings between protein sub-structures are a common property of protein dynamics. Some of these couplings are especially interesting since they relate to function and its regulation. In this article we have studied the case of cavity couplings because cavities can host functional sites, allosteric sites, and are the locus of interactions with the cell milieu. We have divided this problem into two parts. In the first part, we have explored the presence of cavity couplings in the natural dynamics of 75 proteins, using 20 ns molecular dynamics simulations. For each of these proteins, we have obtained two trajectories around their native state. After applying a stringent filtering procedure, we found significant cavity correlations in 60% of the proteins. We analyze and discuss the structure origins of these correlations, including neighbourhood, cavity distance, etc. In the second part of our study, we have used longer simulations (≥100ns) from the MoDEL project, to obtain a broader view of cavity couplings, particularly about their dependence on time. Using moving window computations we explored the fluctuations of cavity couplings along time, finding that these couplings could fluctuate substantially during the trajectory, reaching in several cases correlations above 0.25/0.5. In summary, we describe the structural origin and the variations with time of cavity couplings. We complete our work with a brief discussion of the biological implications of these results.

V67L Mutation Fills an Internal Cavity To Stabilize RecA Mtu Intein

“…Thus, the V67L mutation may rearrange active site geometry and dynamics to enhance intein activity through its effects on cavities. Couplings between cavities in proteins have indeed been demonstrated by MD . Consistent with these ideas, our previous work showed that L2 and N139 experience some of the largest chemical shift perturbations caused by V67L, away from the site of mutation .…”

“…Couplings between cavities in proteins have indeed been demonstrated by MD. 43 Consistent with these ideas, our previous work showed that L2 and N139 experience some of the largest chemical shift perturbations caused by V67L, away from the site of mutation. 14 An additional possibility is that the V67L mutation may affect the intein−extein junctions and intein-extein interaction, which may shift active site conformation and dynamics to favor catalysis.…”

Quantitative Characterization of Binding Pockets and Binding Complementarity by Means of Zernike Descriptors

“…In addition, a useful descriptor should be also able to give information onand possibly, to predictthe interactions between the cavity and the interacting molecules. 27,28 Here, we present a new computational protocol that is able to quantitatively describe both the shape and electrostatic properties of a given subregion of a protein on a rigorous ground by means of a moment-based approach using the Zernike polynomials. 29−31 The main advantage of this method is its ability to describe subregions of a molecular surface in a compact way using a single vector of numbers to provide quantification of both the geometrical shape and the electrostatic potential.…”

Entropy Transfer between Residue Pairs and Allostery in Proteins: Quantifying Allosteric Communication in Ubiquitin

“…Although more than 1000 allosteric sites are known [ 1 ] many more need to be characterized. In fact several pairs of allosteric endpoints may exist in a protein [ 2 ] which increases the number of candidate pairs that communicate. This problem becomes even more important when one considers the fact that most known cancers result from disruption of allosteric communication as a result of single mutations [ 3 , 4 ] and the number of proteins associated with this phenomenon is very large.…”