Guarnera E
Synergistic Allostery in Multiligand-Protein Interactions
Rational 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.
ReadOn the Allosteric Effect of nsSNPs and the Emerging Importance of Allosteric Polymorphism
The 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.
ReadToward Comprehensive Allosteric Control over Protein Activity
Universality 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.
ReadExploring chromatin hierarchical organization via Markov State Modelling
We 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.
ReadOn the perturbation nature of allostery: sites, mutations, and signal modulation
Regardless of the diversity of systems, allosteic signalling is found to be always caused by perturbations. This recurring trait of allostery serves as a foundation for developing different experimental efforts and theoretical models for the studies of allosteric mechanisms. Among computational approaches considered here particular emphasis is given to the structure-based statistical mechanical model of allostery (SBSMMA), which allows one to study the causality and energetics of allosteric communication.
ReadAlloMAPS: allosteric mutation analysis and polymorphism of signaling database
AlloMAPS database provides data on the causality and energetics of allosteric communication obtained with the structure-based statistical mechanical model of allostery (SBSMMA). The database contains data on allosteric signaling in three sets of proteins and protein chains: (i) 46 proteins with comprehensively annotated functional and allosteric sites; (ii) 1908 protein chains from PDBselect set of chains with low (<25%) sequence identity; (iii) 33 proteins with more than 50 known pathological SNPs in each molecule.
ReadReversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response
The omnipresence of allosteric regulation together with the fundamental role of structural dynamics in this phenomenon have initiated a great interest to the detection of regulatory exosites and design of corresponding effectors. However, despite a general consensus on the key role of dynamics most of the earlier efforts on the prediction of allosteric sites are heavily crippled by the static nature of the underlying methods, which are either structure-based approaches seeking for deep surface pockets typical for "traditional" orthosteric drugs or sequence-based techniques exploiting the conservation of protein sequences.
ReadInsulin-Degrading Enzyme in the Fight against Alzheimer's Disease
After decades of research the molecular bases of AD are still under intense discussion. The key features of neuropathology, such as fibril assembly and oligomer neurotoxic activity, are shared between AD and other neurodegenerative diseases, which are caused by peptides nonhomologous to Aβ.
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