Protein Folding Evolution And Design

Protein Folding  Evolution and Design PDF
Author: Eugene I. Shakhnovich
Publisher: IOS Press
ISBN: 9781586031695
Size: 67.31 MB
Format: PDF, ePub
Category : Nature
Languages : en
Pages : 330
View: 4845

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This text presents the results of broad, interdisciplinary effort to study proteins in physical and evolutionary perpective. Among authors are physicists, computational, chemists, crystallographers and evolutionary biologists. Experimental and theoretical developments from molecules to cells are presented, providing a broad picture of modern biophysical chemistry.

Methods In Protein Design

Methods in Protein Design PDF
Author:
Publisher: Academic Press
ISBN: 0123946298
Size: 44.37 MB
Format: PDF, ePub, Mobi
Category : Science
Languages : en
Pages : 520
View: 1526

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This new volume of Methods in Enzymology continues the legacy of this premier serial by containing quality chapters authored by leaders in the field. This volume covers methods in protein design and it has chapters on such topics as protein switch engineering by domain insertion, evolution based design of proteins, and computationally designed proteins. Continues the legacy of this premier serial with quality chapters authored by leaders in the field Covers methods in protein design Contains chapters with such topics as protein switch engineering by domain insertion, evolution-based design of proteins, and computationally designed proteins

From Peptides To Proteins

From Peptides to Proteins PDF
Author: Robert Aron Broom
Publisher:
ISBN:
Size: 35.34 MB
Format: PDF, Mobi
Category :
Languages : en
Pages : 88
View: 6289

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Understanding the origin of protein folds, and the mechanism by which evolution has generated them, is a critically important step on a path towards rational protein design. Modifying existing proteins and designing our own novel folds and functions is a lofty but achievable goal, for which there are many foreseeable rewards. It is believed that modern proteins may have arisen from a primordial set of peptide precursors, which were initially only pseudo-stable or stable only as complexes with RNA, and later were able to self-assemble into multimeric complexes that resembled modern folds. In order to experimentally examine the feasibility of this theory, an attempt was made at reconstructing the evolutionary path of a beta-trefoil. The beta-trefoil is a naturally abundant fold or superfold, possessing pseudo-threefold symmetry, and usually having a sugar-binding function. It has been proposed that such a fold could arise from the triplication of just one small peptide on the order of 40-50 amino acids in length. The evolutionary path of a ricin, a family within the beta-trefoils known to possess a carbohydrate binding function was the chosen template for evolutionary modelling. It was desirable to have a known function associated with this design, such that it would be possible to determine if not only the fold, but also the function, could be reconstructed. A small peptide of 47 amino acids was designed and expressed. This peptide not only trimerized as expected, but possessed the carbohydrate binding function it was predicted to have. In an evolutionary model of the early protein world, the gene for this peptide would undergo duplication and later, triplication, eventually resulting in a completely symmetrical beta-trefoil, which would represent the first modern beta-trefoil fold. Such a completely symmetrical protein was also designed and expressed by triplicating the gene for the aforementioned small peptide. This hypothetical first modern beta-trefoil is: well folded, stable, soluble, and appears to adopt a beta-trefoil fold. Together these results demonstrate that an evolutionary model of early life: that proteins first existed as self-assembling modular peptides, and subsequent to gene duplications or fusions, as what we now recognize as modern folds, is experimentally consistent and not only generates stable structures, but those with function, which of course is a prime requisite of evolution. Moreover the results show that it may be possible to use this modular nature of protein folding to design our own proteins and predict the structure of others.

Evolutionary Algorithms In Molecular Design

Evolutionary Algorithms in Molecular Design PDF
Author: David E. Clark
Publisher: John Wiley & Sons
ISBN: 352761317X
Size: 21.52 MB
Format: PDF, Mobi
Category : Science
Languages : en
Pages : 288
View: 5590

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When trying to find new methods and problem-solving strategies for their research, scientists often turn to nature for inspiration. An excellent example of this is the application of Darwin's Theory of Evolution, particularly the notion of the 'survival of the fittest', in computer programs designed to search for optimal solutions to many kinds of problems. These 'evolutionary algorithms' start from a population of possible solutions to a given problem and, by applying evolutionary principles, evolve successive generations with improved characteristics until an optimal, or near-optimal, solution is obtained. This book highlights the versatility of evolutionary algorithms in areas of relevance to molecular design with a particular focus on drug design. The authors, all of whom are experts in their field, discuss the application of these computational methods to a wide range of research problems including conformational analysis, chemometrics and quantitative structure-activity relationships, de novo molecular design, chemical structure handling, combinatorial library design, and the study of protein folding. In addition, the use of evolutionary algorithms in the determination of structures by X-ray crystallography and NMR spectroscopy is also covered. These state-of-the-art reviews, together with a discussion of new techniques and future developments in the field, make this book a truly valuable and highly up-to-date resource for anyone engaged in the application or development of computer-assisted methods in scientific research.

Protein Folding Dynamics Using Multi Scale Computational Methods

Protein Folding   Dynamics Using Multi scale Computational Methods PDF
Author: Taisong Zou
Publisher:
ISBN:
Size: 28.85 MB
Format: PDF, ePub, Docs
Category : Protein folding
Languages : en
Pages : 144
View: 560

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This thesis explores a wide array of topics related to the protein folding problem, ranging from the folding mechanism, ab initio structure prediction and protein design, to the mechanism of protein functional evolution, using multi-scale approaches. To investigate the role of native topology on folding mechanism, the native topology is dissected into non-local and local contacts. The number of non-local contacts and non-local contact orders are both negatively correlated with folding rates, suggesting that the non-local contacts dominate the barrier-crossing process. However, local contact orders show positive correlation with folding rates, indicating the role of a diffusive search in the denatured basin. Additionally, the folding rate distribution of E. coli and Yeast proteomes are predicted from native topology. The distribution is fitted well by a diffusion-drift population model and also directly compared with experimentally measured half life. The results indicate that proteome folding kinetics is limited by protein half life. The crucial role of local contacts in protein folding is further explored by the simulations of WW domains using Zipping and Assembly Method. The correct formation of N-terminal & beta;-turn turns out important for the folding of WW domains. A classification model based on contact probabilities of five critical local contacts is constructed to predict the foldability of WW domains with 81% accuracy. By introducing mutations to stabilize those critical local contacts, a new protein design approach is developed to re-design the unfoldable WW domains and make them foldable. After folding, proteins exhibit inherent conformational dynamics to be functional. Using molecular dynamics simulations in conjunction with Perturbation Response Scanning, it is demonstrated that the divergence of functions can occur through the modification of conformational dynamics within existing fold for & beta;-lactmases and GFP-like proteins: i) the modern TEM-1 lactamase shows a comparatively rigid active-site region, likely reflecting adaptation for efficient degradation of a specific substrate, while the resurrected ancient lactamases indicate enhanced active-site flexibility, which likely allows for the binding and subsequent degradation of different antibiotic molecules; ii) the chromophore and attached peptides of photocoversion-competent GFP-like protein exhibits higher flexibility than the photocoversion-incompetent one, consistent with the evolution of photocoversion capacity.

Invitation To Protein Sequence Analysis Through Probability And Information

Invitation to Protein Sequence Analysis Through Probability and Information PDF
Author: Daniel J. Graham
Publisher: CRC Press
ISBN: 0429650523
Size: 46.45 MB
Format: PDF, ePub, Mobi
Category : Mathematics
Languages : en
Pages : 292
View: 4521

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This book explores the remarkable information correspondences and probability structures of proteins. Correspondences are pervasive in biochemistry and bioinformatics: proteins share homologies, folding patterns, and mechanisms. Probability structures are just as paramount: folded state graphics reflect Angstrom-scale maps of electron density. The author explores protein sequences (primary structures), both individually and in sets (systems) with the help of probability and information tools. This perspective will enhance the reader’s knowledge of how an important class of molecules is designed and put to task in natural systems, and how we can approach class members in hands-on ways.

Theoretical Studies In Protein Folding

Theoretical Studies in Protein Folding PDF
Author: John Karanicolas
Publisher:
ISBN: 9780599195479
Size: 37.70 MB
Format: PDF, ePub, Docs
Category : Cytochrome c
Languages : en
Pages : 332
View: 4801

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Hemes assume many different roles in nature as protein environments modulate their specific functions. Protein engineering can be used to provide a glimpse into enzyme mechanism by elucidating factors involved in dictating heme specificity and activity. Design of novel function in an enzyme may result in a protein with a specific function or simply explain what interactions are necessary and sufficient for particular activities. Three unique protein engineering investigations in cytochrome c peroxidase (CCP) are described: complementation of the heme iron ligand, introduction of manganese binding and oxidation, and modulation of small substrate activity. First, exogenous imidazole replacement of the axial His ligand results in a complicated series of gated active site modes. Functional, spectroscopic, kinetic, and structural studies suggest that protonated imidazole occupies the cavity created by this mutation and forms a crucial hydrogen bond interaction in the proximal pocket, but does not bind the iron. Neutral imidazole binds the iron, but weakens the hydrogen bond. Since both of these interactions are crucial to formation of an Asp-His-Fe triad in the native protein, imidazole is unable to rescue this mutant. Second, a metal site has been created near the heme, that binds and catalyzes the oxidation of Mn 2+ . Electron transfer from Mn2+ to the ferryl iron is specifically enhanced. Structural studies confirm that Mn2+ interacts with the protein at the site designed. Finally, Ala 147 was replaced by Met and Tyr to investigate the hypothesis that small molecules are oxidized at the o-meso edge of the heme. Crystallographic analyses confirm that the side chains of A147M and A147Y rest over the o-meso position. Steady-state kinetics show that small molecule oxidation is altered to varying degrees depending on the substrate and mutant. These results show that protein engineering is a powerful tool that can be used to address diverse functional questions. These studies have revealed a delicate balance of interactions established by the precise geometry of the native active site, the ability to introduce novel activity, and the existence of multiple mechanisms for small substrate oxidation. Such revelations can lead to further improvements in the cycle of protein design.

Protein Engineering

Protein Engineering PDF
Author:
Publisher:
ISBN:
Size: 61.78 MB
Format: PDF, Docs
Category :
Languages : en
Pages :
View: 3693

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A broad range of topics are covered by providing a solid foundation in protein engineering and supplies readers with knowledge essential to the design and production of proteins. This volume presents in-depth discussions of various methods for protein engineering featuring contributions from leading experts from different counties. A broad series of articles covering significant aspects of methods and applications in the design of novel proteins with different functions are presented. These include the use of non-natural amino acids, bioinformatics, molecular evolution, protein folding and structure-functional insight to develop useful proteins with enhanced properties.

Protein Folding And Drug Design

Protein Folding and Drug Design PDF
Author: R. A. Broglia
Publisher: IOS Press
ISBN: 1586037927
Size: 45.19 MB
Format: PDF, ePub, Mobi
Category : Science
Languages : en
Pages : 308
View: 1408

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"One of the great unsolved problems of science and also physics is the prediction of the three dimensional structure of a protein from its amino acid sequence: the folding problem. It may be stated that the deep connection existing between physics and protein folding is not so much, or in any case not only, through physical methods (experimental: Xrays, NMR, etc, or theoretical: statistical mechanics, spin glasses, etc), but through physical concepts. In fact, protein folding can be viewed as an emergent property not contained neither in the atoms forming the protein nor in the forces acting among them, in a similar way as superconductivity emerges as an unexpected coherent phenomenon taking place on a sea of electrons at low temperature. Already much is known about the protein folding problem, thanks, among other things, to protein engineering experiments as well as from a variety of theoretical inputs: inverse folding problem, funnellike energy landscapes (Peter Wolynes), helixcoil transitions, etc. Although quite different in appearance, the fact that the variety of models can account for much of the experimental ?ndings is likely due to the fact that they contain much of the same (right) physics. A physics which is related to the important role played by selected highly conserved, hot, amino acids which participate to the stability of independent folding units which, upon docking, give rise to a (postcritical) folding nucleus lying beyond the highest maximum of the free energy associated to the process."

Protein Engineering And Design

Protein Engineering and Design PDF
Author: Sheldon J. Park
Publisher: CRC Press
ISBN: 9781420076592
Size: 45.66 MB
Format: PDF, Kindle
Category : Medical
Languages : en
Pages : 416
View: 2258

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Experimental protein engineering and computational protein design are broad but complementary strategies for developing proteins with altered or novel structural properties and biological functions. By describing cutting-edge advances in both of these fields, Protein Engineering and Design aims to cultivate a synergistic approach to protein science

Protein Folding And Drug Design

Protein Folding and Drug Design PDF
Author: R.A. Broglia
Publisher: IOS Press
ISBN: 1607502801
Size: 23.35 MB
Format: PDF, ePub
Category : Medical
Languages : en
Pages : 332
View: 6085

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One of the great unsolved problems of science and also physics is the prediction of the three dimensional structure of a protein from its amino acid sequence: the folding problem. It may be stated that the deep connection existing between physics and protein folding is not so much, or in any case not only, through physical methods (experimental: X–rays, NMR, etc, or theoretical: statistical mechanics, spin glasses, etc), but through physical concepts. In fact, protein folding can be viewed as an emergent property not contained neither in the atoms forming the protein nor in the forces acting among them, in a similar way as superconductivity emerges as an unexpected coherent phenomenon taking place on a sea of electrons at low temperature. Already much is known about the protein folding problem, thanks, among other things, to protein engineering experiments as well as from a variety of theoretical inputs: inverse folding problem, funnel–like energy landscapes (Peter Wolynes), helix–coil transitions, etc. Although quite different in appearance, the fact that the variety of models can account for much of the experimental ?ndings is likely due to the fact that they contain much of the same (right) physics. A physics which is related to the important role played by selected highly conserved, “hot”, amino acids which participate to the stability of independent folding units which, upon docking, give rise to a (post–critical) folding nucleus lying beyond the highest maximum of the free energy associated to the process.

Evolutionary Approaches To Protein Design

Evolutionary Approaches to Protein Design PDF
Author:
Publisher: Elsevier
ISBN: 0080493378
Size: 67.42 MB
Format: PDF, Docs
Category : Science
Languages : en
Pages : 438
View: 972

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This is the first high-quality, comprehensive overview of the field of evolutionary protein design. Topics include new protein design strategies, the structures of laboratory-evolved proteins, the evolution of non-natural enzyme functions, and the theory of laboratory evolution.

Amino Acids Peptides And Proteins

Amino Acids  Peptides and Proteins PDF
Author: G C Barrett
Publisher: Royal Society of Chemistry
ISBN: 1847557430
Size: 52.44 MB
Format: PDF
Category : Science
Languages : en
Pages : 458
View: 3140

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In an ever-increasing domain of activity Amino Acids Peptides and Proteins provides an annual compilation of the world's research effort into this important area of biological chemistry. Volume 33 provides a review of literature published during 2000. Comprising a comprehensive review of significant developments at this biology/chemistry interface each volume opens with an overview of amino acids and their applications. Work on peptides is reviewed over several chapters ranging from current trends in their synthesis and conformational and structural analysis to peptidomimetics and the discovery of peptide-related molecules in nature. The application of advanced techniques in structural elucidation is incorporated into all chapters whilst periodic chapters on metal complexes of amino acids peptides and beta-lactams extend the scope of coverage. Efficient searching of specialist topics is facilitated by the sub-division of chapters into discrete subject areas allowing annual trends to be monitored. All researchers in the pharmaceutical and allied industries and at the biology/chemistry interface in academia will find this an indispensable reference source.

Protein Engineering

Protein Engineering PDF
Author: Mallorie N. Sheehan
Publisher: Nova Science Pub Incorporated
ISBN: 9781626188785
Size: 28.11 MB
Format: PDF, Mobi
Category : Science
Languages : en
Pages : 221
View: 787

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Protein engineering is the process of developing useful or valuable proteins. It is a young discipline, with much research currently taking place into the understanding of protein folding and protein recognition for protein design principles. There are two general strategies for protein engineering. The first is known as rational design, in which the scientist uses detailed knowledge of the structure and function of the protein to make desired changes. The second strategy is known as directed evolution and this is where random mutagenesis is applied to a protein, and a selection regime is used to pick out variants that have the desired qualities. This new book presents and reviews important data on protein engineering, such as application of engineered proteins and cell adhesive surfaces as scaffolds or other biomedical devices which has the potential to promote tissue repair and regeneration for a wide variety of tissues including bone and skin.

Advances In Enzymology And Related Areas Of Molecular Biology

Advances in Enzymology and Related Areas of Molecular Biology PDF
Author: Eric J. Toone
Publisher: John Wiley & Sons
ISBN: 0470891327
Size: 62.35 MB
Format: PDF
Category : Science
Languages : en
Pages : 340
View: 4188

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Advances in Enzymology and Related Areas of Molecular Biology covers the advances in enzymology, explaining the behavior of enzymes and how they can be utilized to develop novel drugs, synthesize known and novel compounds, and understand evolutionary processes.

Computational Design Of Protein Structure And Prediction Of Ligand Binding

Computational Design of Protein Structure and Prediction of Ligand Binding PDF
Author: Robert Aron Broom
Publisher:
ISBN:
Size: 17.93 MB
Format: PDF, ePub
Category : Ligand binding (Biochemistry)
Languages : en
Pages : 251
View: 2861

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Proteins perform a tremendous array of finely-tuned functions which are not only critical in living organisms, but can be used for industrial and medical purposes. The ability to rationally design these molecular machines could provide a wealth of opportunities, for example to improve human health and to expand the range and reduce cost of many industrial chemical processes. The modularity of a protein sequence combined with many degrees of structural freedom yield a problem that can frequently be best tackled using computational methods. These computational methods, which include the use of: bioinformatics analysis, molecular dynamics, empirical forcefields, statistical potentials, and machine learning approaches, amongst others, are collectively known as Computational Protein Design (CPD). Here CPD is examined from the perspective of four different goals: successful design of an intended structure, the prediction of folding and unfolding kinetics from structure (kinetic stability in particular), engineering of improved stability, and prediction of binding sites and energetics. A considerable proportion of protein folds, and the majority of the most common folds ("superfolds"), are internally symmetric, suggesting emergence from an ancient repetition event. CPD, an increasingly popular and successful method for generating de novo folded sequences and topologies, suffers from exponential scaling of complexity with protein size. Thus, the overwhelming majority of successful designs are of relatively small proteins ( 100 amino acids). Designing proteins comprised of repeated modular elements allows the design space to be partitioned into more manageable portions. Here, a bioinformatics analysis of a "superfold", the beta-trefoil, demonstrated that formation of a globular fold via repetition was not only an ancient event, but an ongoing means of generating diverse and functional sequences. Modular repetition also promotes rapid evolution for binding multivalent targets in the "evolutionary arms race" between host and pathogen. Finally, modular repetition was used to successfully design, on the first attempt, a well-folded and functional beta-trefoil, called ThreeFoil. Improving protein design requires understanding the outcomes of design and not simply the 3D structure. To this end, I undertook an extensive biophysical characterization of ThreeFoil, with the key finding that its unfolding is extraordinarily slow, with a half-life of almost a decade. This kinetic stability grants ThreeFoil near-immunity to common denaturants as well as high resistance to proteolysis. A large scale analysis of hundreds of proteins, and coarse-grained modelling of ThreeFoil and other beta-trefoils, indicates that high kinetic stability results from a folded structure rich in contacts between residues distant in sequence (long-range contacts). Furthermore, an analysis of unrelated proteins known to have similar protease resistance, demonstrates that the topological complexity resulting from these long-range contacts may be a general mechanism by which proteins remain folded in harsh environments. Despite the wonderful kinetic stability of ThreeFoil, it has only moderate thermodynamic stability. I sought to improve this in order to provide a stability buffer for future functional engineering and mutagenesis. Numerous computational tools which predict stability change upon point mutation were used, and 10 mutations made based on their recommendations. Despite claims of 80% accuracy for these predictions, only 2 of the 10 mutations were stabilizing. An in-depth analysis of more than 20 such tools shows that, to a large extent, while they are capable of recognizing highly destabilizing mutations, they are unable to distinguish between moderately destabilizing and stabilizing mutations. Designing protein structure tests our understanding of the determinants of protein folding, but useful function is often the final goal of protein engineering. I explored protein-ligand binding using molecular dynamics for several protein-ligand systems involving both flexible ligand binding to deep pockets and more rigid ligand binding to shallow grooves. I also used various levels of simulation complexity, from gas-phase, to implicit solvent, to fully explicit solvent, as well as simple equilibrium simulations to interrogate known interactions to more complex energetically biased simulations to explore diverse configurations and gain novel information.