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Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
processes Review Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development Outi M. H. Salo-Ahen 1,2,* , Ida Alanko 1,2, Rajendra Bhadane 1,2 , Alexandre M. J. J. Bonvin 3,* , Rodrigo Vargas Honorato 3, Shakhawath Hossain 4 , André H. Juffer 5 , Aleksei Kabedev 4, Maija Lahtela-Kakkonen 6, Anders Støttrup Larsen 7, Eveline Lescrinier 8 , Parthiban Marimuthu 1,2 , Muhammad Usman Mirza 8 , Ghulam Mustafa 9, Ariane Nunes-Alves 10,11,* , Tatu Pantsar 6,12, Atefeh Saadabadi 1,2 , Kalaimathy Singaravelu 13 and Michiel Vanmeert 8 1 Pharmaceutical Sciences Laboratory (Pharmacy), Åbo Akademi University, Tykistökatu 6 A, Biocity, FI-20520 Turku, Finland; ida.alanko@abo.fi (I.A.); rajendra.bhadane@abo.fi (R.B.); parthiban.marimuthu@abo.fi (P.M.); atefeh.saadabadi@abo.fi (A.S.) 2 Structural Bioinformatics Laboratory (Biochemistry), Åbo Akademi University, Tykistökatu 6 A, Biocity, FI-20520 Turku, Finland 3 Faculty of Science-Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands; [email protected] 4 Swedish Drug Delivery Forum (SDDF), Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden; [email protected] (S.H.); [email protected] (A.K.) 5 Biocenter Oulu & Faculty of Biochemistry and Molecular Medicine, University of Oulu, Aapistie 7 A, FI-90014 Oulu, Finland; andre.juffer@oulu.fi 6 School of Pharmacy, University of Eastern Finland, FI-70210 Kuopio, Finland; maija.lahtela-kakkonen@uef.fi (M.L.-K.); tatu.pantsar@uef.fi -
Chaotic Descriptor Table
Castle Oldskull Supplement CDT1: Chaotic Descriptor Table These ideas would require a few hours’ the players back to the temple of the more development to become truly useful, serpent people, I decide that she has some but I like the direction that things are going backstory. She’s an old jester-bard so I’d probably run with it. Maybe I’d even treasure hunter who got to the island by redesign dungeon level 4 to feature some magical means. This is simply because old gnome vaults and some deep gnome she’s so far from land and trade routes that lore too. I might even tie the whole it’s hard to justify any other reason for her situation to the gnome caves of C. S. Lewis, to be marooned here. She was captured by or the Nome King from L. Frank Baum’s the serpent people, who treated her as Ozma of Oz. Who knows? chattel, but she barely escaped. She’s delirious, trying to keep herself fed while she struggles to remember the command Example #13: word for her magical carpet. Malamhin of the Smooth Brow has some NPC in the Wilderness magical treasures, including a carpet of flying, a sword, some protection from serpents thingies (scrolls, amulets?) and a The PCs land on a deadly magical island of few other cool things. Talking to the PCs the serpent people, which they were meant and seeing their map will slowly bring her to explore years ago and the GM promptly back to her senses … and she wants forgot about it. -
Open Ratulchowdhury Etd.Pdf
The Pennsylvania State University The Graduate School COMPUTATIONAL REDESIGN OF CHANNEL PROTEINS, ENZYMES, AND ANTIBODIES A Dissertation in Chemical Engineering by Ratul Chowdhury © 2020 Ratul Chowdhury Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2020 The dissertation of Ratul Chowdhury was reviewed and approved* by the following: Costas D. Maranas Donald B. Broughton Professor of Chemical Engineering Dissertation Advisor Chair of Committee Manish Kumar Assistant Professor in Chemical Engineering Michael Janik Professor in Chemical Engineering Reka Albert Professor in Physics Phillip E. Savage Department Head and Graduate Program Chair Professor in Chemical Engineering ii ABSTRACT Nature relies on a wide range of enzymes with specific biocatalytic roles to carry out much of the chemistry needed to sustain life. Proteins catalyze the interconversion of a vast array of molecules with high specificity - from molecular nitrogen fixation to the synthesis of highly specialized hormones, quorum-sensing molecules, defend against disease causing foreign proteins, and maintain osmotic balance using transmembrane channel proteins. Ever increasing emphasis on renewable sources for energy and waste minimization has turned biocatalytic proteins (enzymes) into key industrial workhorses for targeted chemical conversions. Modern protein engineering is central to not only food and beverage manufacturing processes but are also often ingredients in countless consumer product formulations such as proteolytic enzymes in detergents and amylases and peptide-based therapeutics in the form of designed antibodies to combat neurodegenerative diseases (such as Parkinson’s, Alzheimer’s) and outbreaks of Zika and Ebola virus. However, successful protein design or tweaking an existing protein for a desired functionality has remained a constant challenge. -
Recent Advances in Automated Protein Design and Its Future
EXPERT OPINION ON DRUG DISCOVERY 2018, VOL. 13, NO. 7, 587–604 https://doi.org/10.1080/17460441.2018.1465922 REVIEW Recent advances in automated protein design and its future challenges Dani Setiawana, Jeffrey Brenderb and Yang Zhanga,c aDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; bRadiation Biology Branch, Center for Cancer Research, National Cancer Institute – NIH, Bethesda, MD, USA; cDepartment of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA ABSTRACT ARTICLE HISTORY Introduction: Protein function is determined by protein structure which is in turn determined by the Received 25 October 2017 corresponding protein sequence. If the rules that cause a protein to adopt a particular structure are Accepted 13 April 2018 understood, it should be possible to refine or even redefine the function of a protein by working KEYWORDS backwards from the desired structure to the sequence. Automated protein design attempts to calculate Protein design; automated the effects of mutations computationally with the goal of more radical or complex transformations than protein design; ab initio are accessible by experimental techniques. design; scoring function; Areas covered: The authors give a brief overview of the recent methodological advances in computer- protein folding; aided protein design, showing how methodological choices affect final design and how automated conformational search protein design can be used to address problems considered beyond traditional protein engineering, including the creation of novel protein scaffolds for drug development. Also, the authors address specifically the future challenges in the development of automated protein design. Expert opinion: Automated protein design holds potential as a protein engineering technique, parti- cularly in cases where screening by combinatorial mutagenesis is problematic. -
Protein Design Is NP-Hard
Protein Engineering vol.15 no.10 pp.779–782, 2002 Protein Design is NP-hard 1,2 3 Niles A.Pierce and Erik Winfree ri ∈ Ri at each position that minimizes the sum of the pairwise interaction energies between all positions: 1Applied and Computational Mathematics and 3Computer Science and Computation and Neural Systems,California Institute of Technology, ¥ Pasadena, CA 91125, USA Etotal Σ Σ E(ri,rj) Ͻ 2To whom correspondence should be addressed. i j, j i E-mail: [email protected] A solution to this problem is called a global minimum Biologists working in the area of computational protein energy conformation (GMEC). There is currently no known design have never doubted the seriousness of the algo- algorithm for identifying a GMEC solution efficiently (in a rithmic challenges that face them in attempting in silico specific sense to be defined shortly). Given the failure to sequence selection. It turns out that in the language of the identify such an approach, it is worth attempting to discern computer science community, this discrete optimization whether this is even a reasonable goal. Fortunately, a beautiful problem is NP-hard. The purpose of this paper is to theory from computer science allows us to classify the tracta- explain the context of this observation, to provide a simple bility of our problem in terms of other discrete optimization illustrative proof and to discuss the implications for future problems (Garey and Johnson, 1979; Papadimitriou and progress on algorithms for computational protein design. Steiglitz, 1982). This theory does not apply directly to the Keywords: complexity/design/NP-complete/NP-hard/proteins optimization form, but instead to a related decision form that has a ‘yes/no’ answer. -
Renaissance Medals by G· F· Hill and G· Pollard Renaissance Medals from the Samuel H· Kress Collection at the National Gallery of Art
COMPLETE CATALOGUE OF THE SAMUEL H· KRESS COLLECTION RENAISSANCE MEDALS BY G· F· HILL AND G· POLLARD RENAISSANCE MEDALS FROM THE SAMUEL H· KRESS COLLECTION AT THE NATIONAL GALLERY OF ART BASED ON THE CATALOGUE OF RENAISSANCE MEDALS IN THE GUSTAVE DREYFUS COLLECTION BY G·F·HILL REVISED AND ENLARGED BY GRAHAM POLLARD PUBLISHED BY THE PHAIDON PRESS FOR THE SAMUEL H·KRESS FOUNDATION THE REPRODUCTIONS IN THIS VOLUME ARE FROM NBW PHOTOGRAPHS TAKEN BY BULLATY-LOMBO PHOTOGRAPHERS' NBW YORK CITY ALL RIGHTS RESERVED BY PHAIDON PRESS LTD' LONDON SW 7 PRINTED IN GREAT BRITAIN I967 BY ROBERT MACLEIIOSE & CO. LTD A GLASGOW CONTENTS PREFACE page V11 INTRODUCTORY NOTE page IX CATALOGUE page 3 ILLUSTRATIONS page 133 CONCORDANCES page 273 INDEX OF INSCRIPTIONS page 278 GENERAL INDEX page 293 . INDEX OF PERSONS page 300 INDEX OF ARTISTS page 306 PREFACE HE first and only catalogue of the collection of medals formed by Gustave Dreyfus appeared in I93 I. Its author was Sir George Hill, who had studied the collection in depth when it was still T in Dreyfus' hands in the Boulevard Malesherbes in Paris. In a prefatory note, Hill observed that 'keenly as Gustave Dreyfus appreciated all his beautiful things, he had a particularly soft place in his heart for the Italian medals, and ... he would have agreed with the German critic who declared that the medallic art was par excellence the art of the Renaissance, the expression of the quintessence of the spirit of that age.' The preface continues with the tribute: 'His was perhaps the finest collection that has ever been in the hands of a private collector - the "perhaps" might be omitted, but that it is difficult to range the great collections in a true perspective.' Thanks to the Kress Foundation, the Dreyfus collection of medals was not dispersed, like so many other medallic collections, but is preserved intact in the National Gallery of Art in Washington, where it bears out Hill's claim to be regarded as the finest private collection of medals ever to have been formed. -
A British Reflection: the Relationship Between Dante's Comedy and The
A British Reflection: the Relationship between Dante’s Comedy and the Italian Fascist Movement and Regime during the 1920s and 1930s with references to the Risorgimento. Keon Esky A thesis submitted in fulfilment of requirements for the degree of Doctor of Philosophy, Faculty of Arts and Social Sciences. University of Sydney 2016 KEON ESKY Fig. 1 Raffaello Sanzio, ‘La Disputa’ (detail) 1510-11, Fresco - Stanza della Segnatura, Palazzi Pontifici, Vatican. KEON ESKY ii I dedicate this thesis to my late father who would have wanted me to embark on such a journey, and to my partner who with patience and love has never stopped believing that I could do it. KEON ESKY iii ACKNOWLEDGEMENTS This thesis owes a debt of gratitude to many people in many different countries, and indeed continents. They have all contributed in various measures to the completion of this endeavour. However, this study is deeply indebted first and foremost to my supervisor Dr. Francesco Borghesi. Without his assistance throughout these many years, this thesis would not have been possible. For his support, patience, motivation, and vast knowledge I shall be forever thankful. He truly was my Virgil. Besides my supervisor, I would like to thank the whole Department of Italian Studies at the University of Sydney, who have patiently worked with me and assisted me when I needed it. My sincere thanks go to Dr. Rubino and the rest of the committees that in the years have formed the panel for the Annual Reviews for their insightful comments and encouragement, but equally for their firm questioning, which helped me widening the scope of my research and accept other perspectives. -
Commentary Rational Protein Design: Combining Theory and Experiment
Proc. Natl. Acad. Sci. USA Vol. 94, pp. 10015–10017, September 1997 Commentary Rational protein design: Combining theory and experiment H. W. Hellinga* Department of Biochemistry, Duke University Medical Center, Durham, NC 27710 The rational design of protein structure and function is rapidly chosen a priori, kept fixed, and redecorated with different emerging as a powerful approach to test general theories in amino acid sequences that are predicted to be structurally protein chemistry (1). De novo creation of a protein or an compatible with that fold. This ‘‘inverse folding’’ approach (12) active site requires that all the necessary interactions are therefore removes the backbone conformational degrees of provided. The design approach is therefore a way to test the freedom from the design problem. limits of completeness of understanding experimentally. Fur- The first rational design approaches used qualitative rules of thermore, if the experiments are devised in a progressive protein structure applied by inspection (13). These experi- fashion, such that the simplest possible designs are tried first, ments established that it is possible to create sequences de novo followed by iterative additions of more complex interactions that adopt defined structures (1, 14). Furthermore, they dem- until the desired result is achieved, then it may be possible to onstrated that, by following a progressive design strategy [or identify a minimally sufficient set of components. At the center ‘‘hierachic design’’ (1)] in which increasing levels of complexity of the design approach is the ‘‘design cycle,’’ in which theory are iteratively introduced, new insights into the fundamentals and experiment alternate. The starting point is the develop- of protein structure and function can be gained. -
Analyse Et Identification D'acides Aminés Essentiels De L'extension C
UNIVERSITÉ DU QUÉBEC À MONTRÉAL ANALYSE ET IDENTIFICATION D'ACIDES AMINÉS ESSENTIELS DE L'EXTENSION C-TERMINALE DE L'ARN HÉLICASE DBP4 MÉMOIRE PRÉSENTÉ COMME EXIGENCE PARTIELLE DE LA MAÎTRISE EN BIOLOGIE PAR MOHAMED AMINE CHAABANE DÉCEMBRE 2016 UNIVERSITÉ DU QUÉBEC À MONTRÉAL Service des bibliothèques Avertissement La diffusion de ce mémoire se fait dans le respect des droits de son auteur, qui a signé le formulaire Autorisation de reproduire et de diffuser un travail de recherche de cycles supérieurs (SDU-522 - Rév.0?-2011 ). Cette autorisation stipule que «conformément à l'article 11 du Règlement no 8 des études de cycles supérieurs, [l'auteur] concède à l'Université du Québec à Montréal une licence non exclusive d'utilisation et de publication de la totalité ou d'une partie importante de [son] travail de recherche pour des fins pédagogiques et non commerciales. Plus précisément, [l 'auteur] autorise l'Université du Québec à Montréal à reproduire, diffuser, prêter, distribuer ou vendre des copies de [son] travail de recherche à des fins non commerciales sur quelque support que ce soit, y compris l'Internet. Cette licence et cette autorisation n'entraînent pas une renonciation de [la] part [de l'auteur] à [ses] droits moraux ni à [ses] droits de propriété intellectuelle. Sauf entente contraire, [l'auteur] conserve la liberté de diffuser et de commercialiser ou non ce travail dont [il] possède un exemplaire.» RElVIERCIEMENTS ll m'est agréable d'exprimer mes remerciements les plus sincères au Professeur François Dragon pour avoir bien voulu accepter de diriger mon projet de maîtrise. Je suis très reconnaissant envers l'aide qu'il m'a apportée pour bien mener le présent travail avec sa disponibilité, ses encouragements permanents, sa compréhension, son soutien moral et fmancier et sa grande modestie. -
Knowledge Based Protein Design.Pdf
Protein design • Branden & Tooze, Chapter 17 • Protein design is an extreme form of protein engineering, in which the entire polypeptide chain is built in its entirety rather than mutated piecemeal –may or may not involve designing the backbone typically does not use an existing sequence –sometimes called “de novo” protein design to stress the “ground-up” approach • Can be characterized as “inverse protein folding” because one starts from structure and predicts the amino acid sequence • Large number of possible amino acid sequences makes the problem NP-hard –Pierce and Winfree, Protein Engineering 15, 779 (2001) Knowledge-based design Known structures contain information that may be used productively during a design study statistical data, e.g. distribution of amino acids on a helix modeling on a computer Think small and dream big introduce elements to form and stabilize secondary structures hydrophobic patterns on a helix engineer connectivity by introducing turns, loops, Drawbacks • The problem can quickly get out of hand due to the large number of variables that must be evaluated • “Knowledge” is very personal and difficult to objectify Helix bundles Helix bundles are biologically important and common in many structural proteins, transcription factors (coiled coil), and enzymes Stable and soluble—less likely to create run-away oligomers Helices are easier to design de novo because they are stabilized through local interactions, and the factors that contribute to their formation are better understood Easy to characterize experimentally -
Fact Book 2021, No
Fact Book 2021, No. 6.2 A higher degree of healthcare 1 UW Medicine | Fact Book - 2021, No. 6.2 uwmedicine.org/factbook table of contents abbreviated index Accelerate: The Campaign for Our mission is everything . 3 UW Medicine . 6 We improved health from the very beginning . 5 Accountable Care Network . 26 Airlift Northwest . 46 Years of firsts . 7 Awards . 37–41 High awards for distinguished faculty . 10 Buck, Linda B . 11 Care Transformation. 26 A presence around the world . 12 Economic Activity . 6 Finding cures through research . 15 Employees . 6 Fact Sheets . 45–53 One school, five states . 20 Faculty Honors . 11 Healthcare for your entire family . 24 Firsts . .7–9 Fischer, Edmond H . 11 Everyone is included . 31 Graduate Medical Education . 22 Harborview Medical Center . 47 Good health starts in the community . 34 Hartwell, Leland H . 11 Patient care, quality and safety awards . 37 Healthcare Equity Blueprint . 31-32 Improve The Health Of The Public . 34-35 Leading the way . 42 Krebs, Edwin G . 11 Our regional footprint . 44 Leadership . 43 Medical Services . 28-30 Airlift Northwest . 46 National Taiwan University . 6 Harborview Medical Center . 47 Nobel Laureates . 6 Our Values . 4 UW Medical Center . 48 Our Vision . 4 UW Neighborhood Clinics . 49 Partners . 54–56 Patients Are First .. 25 UW Physicians . 50 Patient Visits. 6 UW School of Medicine . 51 Ramsey, MD, Paul G . 42 Research . 15-19 Valley Medical Center . 52 Research Grants . 6 Partners for success . 53 Shanghai Ranking Consultancy . 6 Thomas, E . Donnall. 11 Photo finish . 56 Total Revenue . 6 Index . 57 Uncompensated Care . -
Computational Protein Engineering: Bridging the Gap Between Rational Design and Laboratory Evolution
Int. J. Mol. Sci. 2012, 13, 12428-12460; doi:10.3390/ijms131012428 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review Computational Protein Engineering: Bridging the Gap between Rational Design and Laboratory Evolution Alexandre Barrozo 1, Rok Borstnar 1,2, Gaël Marloie 1 and Shina Caroline Lynn Kamerlin 1,* 1 Department of Cell and Molecular Biology, Uppsala Biomedical Center (BMC), Uppsala University, Box 596, S-751 24 Uppsala, Sweden; E-Mails: [email protected] (A.B.); [email protected] (R.B.); [email protected] (G.M.) 2 Laboratory for BiocomputinG and Bioinformatics, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +46-18-471-4423; Fax: +46-18-530-396. Received: 20 August 2012; in revised form: 16 September 2012 / Accepted: 17 September 2012 / Published: 28 September 2012 Abstract: Enzymes are tremendously proficient catalysts, which can be used as extracellular catalysts for a whole host of processes, from chemical synthesis to the generation of novel biofuels. For them to be more amenable to the needs of biotechnoloGy, however, it is often necessary to be able to manipulate their physico-chemical properties in an efficient and streamlined manner, and, ideally, to be able to train them to catalyze completely new reactions. Recent years have seen an explosion of interest in different approaches to achieve this, both in the laboratory, and in silico. There remains, however, a gap between current approaches to computational enzyme desiGn, which have primarily focused on the early stages of the design process, and laboratory evolution, which is an extremely powerful tool for enzyme redesign, but will always be limited by the vastness of sequence space combined with the low frequency for desirable mutations.