Studies of protein allostery increasingly reveal an involvement of the back and forth order-disorder transitions in this mechanism of protein activity regulation. Here, we investigate the allosteric mechanisms mediated by structural disorder using the structure-based statistical mechanical model of allostery (SBSMMA) that we have previously developed.
ReadThe AlloSigMA 2 server provides an interactive platform for exploring the allosteric signaling caused by ligand binding and/or mutations, for analyzing the allosteric effects of mutations and for detecting potential cancer drivers and pathogenic nsSNPs. It can also be used for searching latent allosteric sites and for computationally designing allosteric effectors for these sites with required agonist/antagonist activity.
ReadRational drug design has traditionally targeted orthosteric sites for common biological ligands such as nucleotides. Loss of specificity is a major disadvantage in such an approach. Allosteric site(s) offer an alternative, and a combination of orthosteric targeting and allosteric drugs offer greater potency and specificity. However, in vitro quantitation of the combinatorial effects of two or more drugs targeting a common protein has remained a challenge. We present a simple method to quantify combinatorial effects in a dual-liganded kinase model by hydrogen-deuterium exchange mass spectrometry. This method is easily scalable for proteins with more than two ligands, as well as for rapid pairwise screening of candidate molecules.
ReadWe review studies of the protein evolution that help to formulate rules for protein design. Acknowledging the fundamental importance of Dayhoff's provision on the emergence of functional proteins from short peptides, we discuss multiple evidences of the omnipresent partitioning of protein globules into structural/functional units, using which greatly facilitates the engineering and design efforts.
ReadThe molecular mechanisms of pathological non-synonymous single-nucleotide polymorphisms are still the object of intensive research. To this end, we explore here whether non-synonymous single-nucleotide polymorphisms can work via allosteric mechanisms. Using structure-based statistical mechanical model of allostery and analyzing energetics of the effects of mutations in a set of 27 proteins with at least 50 pathological SNPs in each molecule, we found that, indeed, some SNPs can work allosterically.
ReadAllosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.
ReadUniversality of allosteric signaling in proteins, molecular machines, and receptors complemented by the great advantages of prospected allosteric drugs in the highly specific, non-competitive, and modulatory nature of their actions calls for deeper theoretical understanding of allosteric communication.
ReadWe propose a new computational method for exploring chromatin structural organization based on Markov State Modelling of Hi-C data represented as an interaction network between genomic loci. A Markov process describes the random walk of a traveling probe in the corresponding energy landscape, mimicking the motion of a biomolecule involved in chromatin function. By studying the metastability of the associated Markov State Model upon annealing, the hierarchical structure of individual chromosomes is observed, and corresponding set of structural partitions is identified at each level of hierarchy.
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