Dynamically Driven Protein Allostery Exhibits Disparate Responses for Fast and Slow Motions

AbstractThere is considerable interest in the dynamic aspect of allosteric action, and in a growing list of proteins allostery has been characterized as being mediated predominantly by a change in dynamics, not a transition in conformation. For considering conformational dynamics, a protein molecule can be simplified into a number of relatively rigid microdomains connected by joints, corresponding to, e.g., communities and edges from a community network analysis. Binding of an allosteric activator strengthens intermicrodomain coupling, thereby quenching fast (e.g., picosecond to nanosecond) local motions but initiating slow (e.g., microsecond to millisecond), cross-microdomain correlated motions that are potentially of functional importance. This scenario explains allosteric effects observed in many unrelated proteins

Prediction of solvent accessibility and sites of deleterious mutations from protein sequence

Residues that form the hydrophobic core of a protein are critical for its stability. A number of approaches have been developed to classify residues as buried or exposed. In order to optimize the classification, we have refined a suite of five methods over a large dataset and proposed a metamethod based on an ensemble average of the individual methods, leading to a two-state classification accuracy of 80%. Many studies have suggested that hydrophobic core residues are likely sites of deleterious mutations, so we wanted to see to what extent these sites can be predicted from the putative buried residues. Residues that were most confidently classified as buried were proposed as sites of deleterious mutations. This proposition was tested on six proteins for which sites of deleterious mutations have previously been identified by stability measurement or functional assay. Of the total of 130 residues predicted as sites of deleterious mutations, 104 (or 80%) were correct

Transfer Free Energies of Test Proteins Into Crowded Protein Solutions Have Simple Dependence on Crowder Concentration

The effects of macromolecular crowding on the thermodynamic properties of test proteins are determined by the latter's transfer free energies from a dilute solution to a crowded solution. The transfer free energies in turn are determined by effective protein-crowder interactions. When these interactions are modeled at the all-atom level, the transfer free energies may defy simple predictions. Here we investigated the dependence of the transfer free energy (Δμ) on crowder concentration. We represented both the test protein and the crowder proteins atomistically, and used a general interaction potential consisting of hard-core repulsion, non-polar attraction, and solvent-screened electrostatic terms. The chemical potential was rigorously calculated by FMAP (Qin and Zhou, 2014), which entails expressing the protein-crowder interaction terms as correlation functions and evaluating them via fast Fourier transform (FFT). To high accuracy, the transfer free energy can be decomposed into an excluded-volume component (Δμe−v), arising from the hard-core repulsion, and a soft-attraction component (Δμs−a), arising from non-polar and electrostatic interactions. The decomposition provides physical insight into crowding effects, in particular why such effects are very modest on protein folding stability. Further decomposition of Δμs−a into non-polar and electrostatic components does not work, because these two types of interactions are highly correlated in contributing to Δμs−a. We found that Δμe−v fits well to the generalized fundamental measure theory (Qin and Zhou, 2010), which accounts for atomic details of the test protein but approximates the crowder proteins as spherical particles. Most interestingly, Δμs−a has a nearly linear dependence on crowder concentration. The latter result can be understood within a perturbed virial expansion of Δμ (in powers of crowder concentration), with Δμe−v as reference. Whereas the second virial coefficient deviates strongly from that of the reference system, higher virial coefficients are close to their reference counterparts, thus leaving the linear term to make the dominant contribution to Δμs−a