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Current Opinion in Structural Biology

Paweł Śledź, Amedeo Caflisch
Recent years have witnessed rapid developments of computer-aided drug design methods, which have reached accuracy that allows their routine practical applications in drug discovery campaigns. Protein structure-based methods are useful for the prediction of binding modes of small molecules and their relative affinity. The high-throughput docking of up to 10(6) small molecules followed by scoring based on implicit-solvent force field can robustly identify micromolar binders using a rigid protein target. Molecular dynamics with explicit solvent is a low-throughput technique for the characterization of flexible binding sites and accurate evaluation of binding pathways, kinetics, and thermodynamics...
November 14, 2017: Current Opinion in Structural Biology
Anna Pabis, Valeria A Risso, Jose M Sanchez-Ruiz, Shina Cl Kamerlin
Enzymes are flexible catalysts, and there has been substantial discussion about the extent to which this flexibility contributes to their catalytic efficiency. What has been significantly less discussed is the extent to which this flexibility contributes to their evolvability. Despite this, recent years have seen an increasing number of both experimental and computational studies that demonstrate that cooperativity and flexibility play significant roles in enzyme innovation. This review covers key developments in the field that emphasize the importance of enzyme dynamics not just to the evolution of new enzyme function(s), but also as a property that can be harnessed in the design of new artificial enzymes...
November 12, 2017: Current Opinion in Structural Biology
Yong Wang, Katrine Bugge, Birthe B Kragelund, Kresten Lindorff-Larsen
Cells are dependent on transmembrane receptors to communicate and transform chemical and physical signals into intracellular responses. Because receptors transport 'information', conformational changes and protein dynamics play a key mechanistic role. We here review examples where experiment and computation have been used to study receptor dynamics. Recent studies on three distinct classes of receptors (G-protein coupled receptors, ligand-gated ion-channels and single-pass receptors) are highlighted to show that conformational changes across a range of time-scales and length-scales are central to function...
November 11, 2017: Current Opinion in Structural Biology
Neil J Bruce, Gaurav K Ganotra, Daria B Kokh, S Kashif Sadiq, Rebecca C Wade
The recent and growing evidence that the efficacy of a drug can be correlated to target binding kinetics has seeded the development of a multitude of novel methods aimed at computing rate constants for receptor-ligand binding processes, as well as gaining an understanding of the binding and unbinding pathways and the determinants of structure-kinetic relationships. These new approaches include various types of enhanced sampling molecular dynamics simulations and the combination of energy-based models with chemometric analysis...
November 10, 2017: Current Opinion in Structural Biology
G Tiana, L Giorgetti
Eukaryotic chromosomes are complex polymers, which largely exceed in size most biomolecules that are usually modelled in computational studies and whose molecular interactions are to a large extent unknown. Since the folding of the chromatin fiber in the cell nucleus is tightly linked to biological function and gene expression in particular, characterizing the conformational and dynamical properties of chromosomes has become crucial in order to better understand how genes are regulated. In parallel with the development of experimental techniques allowing to measure physical contacts within chromosomes inside the cell nucleus, a large variety of physical models to study the structure and mechanisms of chromosome folding have recently emerged...
November 8, 2017: Current Opinion in Structural Biology
Eleanor C Campbell, Galen J Correy, Peter D Mabbitt, Ashley M Buckle, Nobuhiko Tokiriki, Colin J Jackson
This review focuses on recent work that has begun to establish specific functional roles for protein conformational dynamics, specifically how the conformational landscapes that proteins can sample can evolve under laboratory based evolutionary selection. We discuss recent technical advances in computational and biophysical chemistry, which have provided us with new ways to dissect evolutionary processes. Finally, we offer some perspectives on the emerging view of conformational dynamics and evolution, and the challenges that we face in rationally engineering conformational dynamics...
November 7, 2017: Current Opinion in Structural Biology
Jay F Storz
Adaptive protein evolution may be facilitated by neutral amino acid mutations that confer no benefit when they first arise but which potentiate subsequent function-altering mutations via direct or indirect structural mechanisms. Theoretical and empirical results indicate that such compensatory interactions (intramolecular epistasis) can exert a strong influence on trajectories of protein evolution. For this reason, assessing the form and prevalence of intramolecular epistasis and characterizing biophysical mechanisms of compensatory interaction are important research goals at the nexus of structural biology and molecular evolution...
November 5, 2017: Current Opinion in Structural Biology
Mohamed A Ghadie, Jasmin Coulombe-Huntington, Yu Xia
We highlight new evolutionary insights enabled by recent genome-wide studies on protein-protein interaction (PPI) networks ('interactomes'). While most PPIs are mediated by a single sequence region promoting or inhibiting interactions, many PPIs are mediated by multiple sequence regions acting cooperatively. Most PPIs perform important functions maintained by negative selection: we estimate that less than ∼10% of the human interactome is effectively neutral upon perturbation (i.e. 'junk' PPIs), and the rest are deleterious upon perturbation; interfacial sites evolve more slowly than other sites; many conserved PPIs show signatures of co-evolution at the interface; PPIs evolve more slowly than protein sequence...
November 4, 2017: Current Opinion in Structural Biology
Carmela Garcia-Doval, Martin Jinek
Prokaryotic Class 2 CRISPR-Cas systems mediate adaptive immunity against invasive genetic elements by means of standalone effector proteins that function as RNA-guided nucleases. The effectors Cas9 and Cas12 generate double-strand breaks in DNA substrates, which has been exploited for genome editing applications. In turn, Cas13 enzymes function as RNA-guided ribonucleases whose non-specific activity is triggered by target RNA binding. In this review, we highlight recent structural investigations of Cas9, Cas12 and Cas13 nucleases that have illuminated many aspects of their molecular mechanisms...
November 3, 2017: Current Opinion in Structural Biology
Paulo As Mourão, Eduardo Vilanova, Paulo Ag Soares
Sulfated fucans from marine invertebrates are composed of regular repetitive fucose building-blocks with sulfation patterns differing in a species-specific manner. These polysaccharides can act as mediators of the acrosome reaction of sea-urchins or play a structural role in the body-wall of sea-cucumbers. Other fucose-rich polysaccharides found in the body-wall of sea-cucumbers are the fucosylated chondroitin sulfates composed of a vertebrate-like chondroitin sulfate decorated with species-specific fucose branches...
November 2, 2017: Current Opinion in Structural Biology
Hendrik Szurmant, Martin Weigt
Interacting proteins coevolve at multiple but interconnected scales, from the residue-residue over the protein-protein up to the family-family level. The recent accumulation of enormous amounts of sequence data allows for the development of novel, data-driven computational approaches. Notably, these approaches can bridge scales within a single statistical framework. Although being currently applied mostly to isolated problems on single scales, their immense potential for an evolutionary informed, structural systems biology is steadily emerging...
November 1, 2017: Current Opinion in Structural Biology
Diego U Ferreiro, Elizabeth A Komives, Peter G Wolynes
Natural protein molecules are exceptional polymers. Encoded in apparently random strings of amino-acids, these objects perform clear physical tasks that are rare to find by simple chance. Accurate folding, specific binding, powerful catalysis, are examples of basic chemical activities that the great majority of polypeptides do not display, and are thought to be the outcome of the natural history of proteins. Function, a concept genuine to Biology, is at the core of evolution and often conflicts with the physical constraints...
November 1, 2017: Current Opinion in Structural Biology
Veronika Csizmok, Julie D Forman-Kay
Post-translational modifications (PTMs), which are found largely in intrinsically disordered protein regions (IDRs), regulate protein activity, stability and interactions with partners. They are therefore critical for controlling essentially all cellular processes. A single modification event can have dramatic effects; however, proteins are often modified on multiple sites to collectively modulate the biological outcome. Multiple PTMs can mediate the same, complementary or opposing effects and the result of their interplay is determined by a complex combination of the number, positioning and type of modifications...
October 31, 2017: Current Opinion in Structural Biology
John Bo Mitchell
With rapid increases over recent years in the determination of protein sequence and structure, alongside knowledge of thousands of enzyme functions and hundreds of chemical mechanisms, it is now possible to combine breadth and depth in our understanding of enzyme evolution. Phylogenetics continues to move forward, though determining correct evolutionary family trees is not trivial. Protein function prediction has spawned a variety of promising methods that offer the prospect of identifying enzymes across the whole range of chemical functions and over numerous species...
October 27, 2017: Current Opinion in Structural Biology
Giuliana Fusco, Maximo Sanz-Hernandez, Alfonso De Simone
α-Synuclein (αS) is a neuronal protein that localises predominantly at the presynaptic terminals, and whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson's disease. In vivo αS is partitioned between water-soluble and membrane-bound states, and this highly regulated equilibrium influences its biological behaviour under both physiological and pathological conditions. Here we discuss the sequence and structural determinants underlying the transition between the unstructured cytosolic and partially structured membrane-bound states of αS...
October 27, 2017: Current Opinion in Structural Biology
Konstantinos D Tsirigos, Sudha Govindarajan, Claudio Bassot, Åke Västermark, John Lamb, Nanjiang Shu, Arne Elofsson
Transmembrane proteins perform a variety of important biological functions necessary for the survival and growth of the cells. Membrane proteins are built up by transmembrane segments that span the lipid bilayer. The segments can either be in the form of hydrophobic alpha-helices or beta-sheets which create a barrel. A fundamental aspect of the structure of transmembrane proteins is the membrane topology, that is, the number of transmembrane segments, their position in the protein sequence and their orientation in the membrane...
October 26, 2017: Current Opinion in Structural Biology
Anna Tramontano
The function of proteins in the cell is almost always mediated by their interaction with different partners, including other proteins, nucleic acids or small organic molecules. The ability of identifying all of them is an essential step in our quest for understanding life at the molecular level. The inference of the protein complex composition and of its molecular details can also provide relevant clues for the development and the design of drugs. In this short review, I will discuss the computational aspects of the analysis and prediction of protein-protein assemblies and discuss some of the most recent developments as seen in the last Critical Assessment of Techniques for Protein Structure Prediction (CASP) experiment...
October 25, 2017: Current Opinion in Structural Biology
Joe G Greener, Michael Je Sternberg
Allostery is the functional change at one site on a protein caused by a change at a distant site. In order for the benefits of allostery to be taken advantage of, both for basic understanding of proteins and to develop new classes of drugs, the structure-based prediction of allosteric binding sites, modulators and communication pathways is necessary. Here we review the recently emerging field of allosteric prediction, focusing mainly on computational methods. We also describe the search for cryptic binding pockets and attempts to design allostery into proteins...
October 25, 2017: Current Opinion in Structural Biology
Jing Huang, Alexander D MacKerell
Intrinsically disordered proteins (IDPs) play important roles in many physiological processes such as signal transduction and transcriptional regulation. Computer simulations that are based on empirical force fields have been increasingly used to understand the biophysics of disordered proteins. In this review, we focus on recent improvement of protein force fields, including polarizable force fields, concerning their accuracy in modeling intrinsically disordered proteins. Some recent benchmarks and applications of these force fields are also overviewed...
October 25, 2017: Current Opinion in Structural Biology
Hoi Sung Chung, William A Eaton
The transition path is the tiny segment of a single molecule trajectory when the free energy barrier between states is crossed and for protein folding contains all of the information about the self-assembly mechanism. As a first step toward obtaining structural information during the transition path from experiments, single molecule FRET spectroscopy has been used to determine average transition path times from a photon-by-photon analysis of fluorescence trajectories. These results, obtained for several different proteins, have already provided new and demanding tests that support both the accuracy of all-atom molecular dynamics simulations and the basic postulates of energy landscape theory of protein folding...
October 25, 2017: Current Opinion in Structural Biology
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