Evolutionary Insights Into Protein Structure, Stability, and Functionality PDF Download
Are you looking for read ebook online? Search for your book and save it on your Kindle device, PC, phones or tablets. Download Evolutionary Insights Into Protein Structure, Stability, and Functionality PDF full book. Access full book title Evolutionary Insights Into Protein Structure, Stability, and Functionality by Paul Douglas Williams. Download full books in PDF and EPUB format.
Author: Paul Douglas Williams
Publisher:
ISBN:
Category :
Languages : en
Pages : 222
Get Book Here
Book Description
Author: Paul Douglas Williams
Publisher:
ISBN:
Category :
Languages : en
Pages : 222
Get Book Here
Book Description
Author: Jeffrey M. Koshi
Publisher:
ISBN:
Category :
Languages : en
Pages : 192
Get Book Here
Book Description
Author: Philip W. Bransford
Publisher:
ISBN:
Category :
Languages : en
Pages : 145
Get Book Here
Book Description
The volume of protein structure data has grown rapidly over the past 30 years, leaving a wake of facts that still require explanation. We endeavored to answer a few open questions on the structure-function relationship of intriguing mechanochemical protein systems. To this end this thesis work contains five studies that offer novel insights into molecular biomechanical systems that may guide future basic research or applications development. The first study concerns the biophysics of cadherin-mediated cell sorting observed in developing solid tissue. We investigated the evolutionary dynamics of the cadherin superfamily of cell-cell adhesion proteins to infer a structural basis for their paradoxical mixture of pairwise binding specificity and promiscuity. Our analysis predicts a small set of specificity-determining residues located within the protomer-protomer binding interface. The putative specificity-determinants form a design space with potential for engineering novel cell-cell adhesive interactions. The second study addresses the open question of how to automatically identify regions within a protein that engage in allosteric communication. To identify allostery we developed and tested two computational tools that operate on protein conformational dynamics data. These tools are useful for generating testable hypotheses about proteins with multiple functional sites for the design of non-competitive protein inhibitors. The third study asks, "What is the consequence of allosteric cooperation between the tandem binding sites in a class of proteins that bundle filamentous actin (F-actin)?" Through simulation we demonstrate that cooperative F-actin bundling tends to strengthen bundles by driving the formation of cross-links between neighboring filaments while depleting F-actin binding sites that are occupied but not cross-linked. We hence propose that allostery may be a natural feature of ABPs with tandem F-actin binding sites if nature indeed selects for sturdy F-actin bundles. The final two studies examine the impact of two structural perturbations to Factin on its mechanics. Using structure-based computer modeling we develop a simple explanation for the mechanism by which the structure of actin's polymorphic subdomain 2 mediates 4-fold changes in F-actin's flexibility. We further demonstrate that two calponin homology domains stabilize F-actin by binding in a configuration that tends to relax the stress concentration at actin-actin interfaces.
Author: Robert Pilstål
Publisher: Linköping University Electronic Press
ISBN: 9176853470
Category :
Languages : en
Pages : 206
Get Book Here
Book Description
We are compounded entities, given life by a complex molecular machinery. When studying these molecules we have to make sense of a diverse set of dynamical nanostructures with wast and intricate patterns of interactions. Protein polymers is one of the major groups of building blocks of such nanostructures which fold up into more or less distinct three dimensional structures. Due to their shape, dynamics and chemical properties proteins are able to perform a plethora of specific functions essential to all known cellular lifeforms. The connection between protein sequence, translated into protein structure and in the continuation into protein function is well accepted but poorly understood. Malfunction in the process of protein folding is known to be implicated in natural aging, cancer and degenerative diseases such as Alzheimer's. Protein folds are described hierarchically by structural ontologies such as SCOP, CATH and Pfam all which has yet to succeed in deciphering the natural language of protein function. These paradigmatic views centered on protein structure fail to describe more mutable entities, such as intrinsically disordered proteins (IDPs) which lack a clear defined structure. As of 2012, about two thirds of cancer patients was predicted to survive past 5 years of diagnosis. Despite this, about a third do not survive and numerous of successfully treated patients suffer from secondary conditions due to chemotherapy, surgery and the like. In order to handle cancer more efficiently we have to better understand the underlying molecular mechanisms. Elusive to standard methods of investigation, IDPs have a central role in pathology; dysfunction in IDPs are key factors in cellular system failures such as cancer, as many IDPs are hub regulators for major cell functions. These IDPs carry short conserved functional boxes, that are not described by known ontologies, which suggests the existence of a smaller entity. In an investigation of a pair of such boxes of c-MYC, a plausible structural model of its interacting with Pin1 emerged, but such a model still leaves the observer with a puzzle of understanding the actual function of that interaction. If the protein is represented as a graph and modeled as the interaction patterns instead of as a structural entity, another picture emerges. As a graph, there is a parable from that of the boxes of IDPs, to that of sectors of allosterically connected residues and the theory of foldons and folding units. Such a description is also useful in deciphering the implications of specific mutations. In order to render a functional description feasible for both structured and disordered proteins, there is a need of a model separate from form and structure. Realized as protein primes, patterns of interaction, which has a specific function that can be defined as prime interactions and context. With function defined as interactions, it might be possible that the discussion of proteins and their mechanisms is thereby simplified to the point rendering protein structural determination merely supplementary to understanding protein function. Människan byggs upp av celler, de i sin tur består av än mindre beståndsdelar; livets molekyler. Dessa fungerar som mekaniska byggstenar, likt maskiner och robotar som sliter vid fabrikens band; envar utförandes en absolut nödvändig funktion för cellens, och hela kroppens, fortsatta överlevnad. De av livets molekyler som beskrivs centralt i den här avhandling är proteiner, vilka i sin tur består utav en lång kedja, med olika typer av länkar, som likt garn lindar upp sig i ett nystan av en (mer eller mindre...) bestämd struktur som avgör dess roll och funktion i cellen. Intrinsiellt oordnade proteiner (IDP) går emot denna enkla åskådning; de är proteiner som saknar struktur och beter sig mer likt spaghetti i vatten än en maskin. IDP är ändå funktionella och bär på centrala roller i cellens maskineri; exempel är oncoproteinet c-Myc som agerar "gaspedal" för cellen - fel i c-Myc's funktion leder till att cellerna löper amok, delar sig hejdlöst och vi får cancer. Man har upptäckt att c-Myc har en ombytlig struktur vi inte kan se; studier av punktvisa förändringar, mutationer, i kedjan av byggstenar hos c-Myc visar att många länkar har viktiga roller i funktionen. Detta ger oss bättre förståelse om cancer men samtidigt är laboratoriearbetet både komplicerat och dyrt; här kan evolutionen vägleda oss och avslöja hemligheterna snabbare. Molekylär evolution studeras genom att beräkna variation i proteinkedjan mellan besläktade arter som finns lagrade i databaser; detta visar snabbt, via nätverksanalys och grafteori, vilka delar av proteinet som är centrala och kopplade till varandra av nödvändighet för artens fortlevnad. På så vis hjälper evolutionen oss att förstå proteinfunktioner via modeller baserade på proteinernas interaktioner snarare än deras struktur. Samma modeller kan nyttjas för att förstå dynamiska förlopp och skillnader mellan normala och patologiska varianter av proteiner; mutationer kan uppstå i vår arvsmassa som kan leda till sjukdom. Genom analys av proteinernas kopplingsnätverk i grafmodellerna kan man bättre förutsäga vilka mutationer som är farligare än andra. Dessutom har det visat sig att en sådan representation kan ge bättre förståelse för den normala funktionen hos ett protein än vad en proteinstruktur kan. Här introduceras även konceptet proteinprimärer, vilket är en abstrakt representation av proteiner centrerad på deras interaktiva mönster, snarare än på partikulär form och struktur. Det är en förhoppning att en sådan representation skall förenkla diskussionen anbelangande proteinfunktion så till den grad att strukturbestämmelse av proteiner, som är en mycket kostsam och tidskrävande process, till viss mån kan anses vara sekundär i betydelse jämfört med funktionellt modellerande baserat på evolutionära data extraherade ur våra sekvensdatabaser.
Author: N. A. Kolchanov
Publisher: World Scientific
ISBN: 9789810213787
Category : Science
Languages : en
Pages : 590
Get Book Here
Book Description
Molecular biology and genetics are fast-growing fields with significant results and findings being reported virtually every day. Raw data from the wet lab accumulate at an astonishing rate, making it necessary to analyze the biological data with the use of computers. This book reveals how the current challenges of molecular biology and genetics are met with computer and mathematical treatments. A combined effort of the Computational Genetics and Biophysics Group (Supercomputer Computations Research Institute, USA), the Theoretical Molecular Genetics (Russian Academy of Sciences, Russia) and the Bioinformatics Group (Consiglio Nazionale delle Ricerche, Italy), many of these findings are firsthand discoveries made by these groups. The book emphasizes the fundamental principles of the structural-functional organization of the 3 major classes of genetic macromolecules: DNA, RNA and proteins. It also introduces universally applicable theoretical principles into the enormous realm of raw data and develops an integrative, theoretical computer approach to the analysis of these macromolecules to gain insights into the complexities of their function and evolution.
Author: Johan A. Grahnen
Publisher:
ISBN: 9781303049668
Category : Bioinformatics
Languages : en
Pages : 278
Get Book Here
Book Description
Protein structure and function have profound impact on the evolution of coding sequences. In ordered proteins, correct folding into the native conformation is a prerequisite for proper function and fitness, and is therefore always under selection. Affinity and specificity of binding form one crucial aspect of protein function, and the biophysical mechanisms that govern both processes constrain the manner in which they can evolve. Their maintenance in the face of deleterious mutations, and the evolution of novel beneficial functions, influences which changes are possible from the level of individual residues up to the content of whole genomes. Models of sequence evolution typically ignore these factors, but in this work it is shown that taking them into account improves our understanding of the process considerably. To better understand the influence of structure, a model system for simulating the impact of mutations on thermodynamics of protein folding stability and binding function was developed. As one must evaluate a vast number of mutations to study the highly stochastic process of evolution, a coarse-grained model of the structural consequences of point mutations was first constructed. It compared favorably with state-of-the-art methods for accuracy and showed over an order of magnitude improvement in computational efficiency. Next, a biophysically inspired model for scoring the thermodynamic consequences of mutations was added. This full framework reproduced some characteristics of natural protein sequence evolution, and shed light on fundamental problems plaguing structure-based models. With this model system in hand, the evolutionary interdependence between sites caused by protein structure was examined. Through simulation, it was found that selection for folding alone can cause shifts in the rate of evolution. As this had previously been thought to be a hallmark of changes in protein function, further simulations under selection for novel function showed that the rate shifts caused by changing selection on function are extremely difficult to differentiate from those caused by constant selection on folding. These results suggest that the baseline expectation of evolutionary rates under different types of selection must be modified to take the effects of protein structure into account, and that detection of functional shifts from protein sequence data needs to involve structural considerations. Finally, the impact of protein structure on genome content was examined. It had previously been suggested that selection for organism-specific function was responsible for observed differences in distribution of protein folds between genomes. However, selection is weak compared to neutral processes in organisms with a small effective population size, and other factors must influence genomic fold abundance there. Through modeling of changes in genome content in the Metazoans, it was found that structurally mediated evolvability explains a small but significant fraction of variation in the fold distribution. If the result is robust, it suggests that expectations of neutral genome evolution depend on structure, and that there are implications for adaptive evolution in weak selective regimes in general. As a whole, this work highlights the necessity of considering selection on thermodynamics of structure and function when making inferences about the past states and evolution of protein sequences. There is no such thing as purely neutral evolution of expressed proteins, and the mechanisms governing folding and function are of critical importance when it comes to interpreting sequence data.
Author: Ivet Bahar
Publisher: Garland Science
ISBN: 1351815016
Category : Science
Languages : en
Pages : 337
Get Book Here
Book Description
Protein Actions: Principles and Modeling is aimed at graduates, advanced undergraduates, and any professional who seeks an introduction to the biological, chemical, and physical properties of proteins. Broadly accessible to biophysicists and biochemists, it will be particularly useful to student and professional structural biologists and molecular biophysicists, bioinformaticians and computational biologists, biological chemists (particularly drug designers) and molecular bioengineers. The book begins by introducing the basic principles of protein structure and function. Some readers will be familiar with aspects of this, but the authors build up a more quantitative approach than their competitors. Emphasizing concepts and theory rather than experimental techniques, the book shows how proteins can be analyzed using the disciplines of elementary statistical mechanics, energetics, and kinetics. These chapters illuminate how proteins attain biologically active states and the properties of those states. The book ends with a synopsis the roles of computational biology and bioinformatics in protein science.
Author: Kenneth P. Murphy
Publisher: Springer Science & Business Media
ISBN: 1592591930
Category : Science
Languages : en
Pages : 258
Get Book Here
Book Description
In Protein Structure, Stability, and Folding, Kenneth P. Murphy and a panel of internationally recognized investigators describe some of the newest experimental and theoretical methods for investigating these critical events and processes. Among the techniques discussed are the many methods for calculating many of protein stability and dynamics from knowledge of the structure, and for performing molecular dynamics simulations of protein unfolding. New experimental approaches presented include the use of co-solvents, novel applications of hydrogen exchange techniques, temperature-jump methods for looking at folding events, and new strategies for mutagenesis experiments. Unique in its powerful combination of theory and practice, Protein Structure, Stability, and Folding offers protein and biophysical chemists the means to gain a more comprehensive understanding of some of this complex area by detailing many of the major techniques in use today.
Author: Jay F. Storz
Publisher:
ISBN: 0198810687
Category : Medical
Languages : en
Pages : 258
Get Book Here
Book Description
Provides a synthesis of our current understanding of hemoglobin (Hb) function and evolution, and illustrates how research on this protein has provided more general insights into mechanisms of protein evolution and biochemical adaptation.
Author: Alexei V. Finkelstein
Publisher: Elsevier
ISBN: 0081012365
Category : Science
Languages : en
Pages : 530
Get Book Here
Book Description
Protein Physics: A Course of Lectures covers the most general problems of protein structure, folding and function. It describes key experimental facts and introduces concepts and theories, dealing with fibrous, membrane, and water-soluble globular proteins, in both their native and denatured states. The book systematically summarizes and presents the results of several decades of worldwide fundamental research on protein physics, structure, and folding, describing many physical models that help readers make estimates and predictions of physical processes that occur in proteins. New to this revised edition is the inclusion of novel information on amyloid aggregation, natively disordered proteins, protein folding in vivo, protein motors, misfolding, chameleon proteins, advances in protein engineering & design, and advances in the modeling of protein folding. Further, the book provides problems with solutions, many new and updated references, and physical and mathematical appendices. In addition, new figures (including stereo drawings, with a special appendix showing how to use them) are added, making this an ideal resource for graduate and advanced undergraduate students and researchers in academia in the fields of biophysics, physics, biochemistry, biologists, biotechnology, and chemistry. Fully revised and expanded new edition based on the latest research developments in protein physics Written by the world's top expert in the field Deals with fibrous, membrane, and water-soluble globular proteins, in both their native and denatured states Summarizes, in a systematic form, the results of several decades of worldwide fundamental research on protein physics and their structure and folding Examines experimental data on protein structure in the post-genome era
