Project acronym EASTFE3
Project Efficient and accurate simulation techniques for free energies, enthalpies and entropies
Researcher (PI) Bernard Christiaan Oostenbrink
Host Institution (HI) UNIVERSITAET FUER BODENKULTUR WIEN
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Computational, structure-based, drug design offers insight at an atomic resolution, which is commonly not attainable by experimental means. Detailed calculations on protein-ligand interactions help to rationalize and predict experimental findings. Accurate and efficient calculations of binding free energies is essential in this respect. In addition, knowledge concerning the enthalpic and entropic contributions are highly relevant to determine novel drug design strategies and to understand the underlying principles of ligand binding.
Currently available methods to address ligand affinity either do not include all relevant contributions to the binding free energy, or are too computationally demanding to be applied straightforwardly. In addition, calculations on enthalpy and entropy for drug design purposes are very rare, due to the difficulty in calculating these accurately. This proposal describes the research that leads the way to new, standard applications to be used in drug design processes in academia and industry. Furthermore, we propose to investigate the enthalpic and entropic contributions to ligand binding. We define a ligand-surroundings enthalpy and entropy, which conveys more information than the experimentally accessible enthalpy and entropy of ligand binding.
In support of this research, we will develop new enhanced sampling techniques which not only render the above calculations practically feasible, but which will also find their application in related research questions such as the protein folding problem or the elucidation of protein-protein interactions.
The methods described are highly relevant for the pharmaceutical industry, where currently available computational approaches are insufficient to answer the questions of todays drug discovery programmes.
Summary
Computational, structure-based, drug design offers insight at an atomic resolution, which is commonly not attainable by experimental means. Detailed calculations on protein-ligand interactions help to rationalize and predict experimental findings. Accurate and efficient calculations of binding free energies is essential in this respect. In addition, knowledge concerning the enthalpic and entropic contributions are highly relevant to determine novel drug design strategies and to understand the underlying principles of ligand binding.
Currently available methods to address ligand affinity either do not include all relevant contributions to the binding free energy, or are too computationally demanding to be applied straightforwardly. In addition, calculations on enthalpy and entropy for drug design purposes are very rare, due to the difficulty in calculating these accurately. This proposal describes the research that leads the way to new, standard applications to be used in drug design processes in academia and industry. Furthermore, we propose to investigate the enthalpic and entropic contributions to ligand binding. We define a ligand-surroundings enthalpy and entropy, which conveys more information than the experimentally accessible enthalpy and entropy of ligand binding.
In support of this research, we will develop new enhanced sampling techniques which not only render the above calculations practically feasible, but which will also find their application in related research questions such as the protein folding problem or the elucidation of protein-protein interactions.
The methods described are highly relevant for the pharmaceutical industry, where currently available computational approaches are insufficient to answer the questions of todays drug discovery programmes.
Max ERC Funding
1 485 615 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym EFFECTOMICS
Project EFFECTOMICS- elucidating the toolbox of
biotrophic pathogens
Researcher (PI) Armin Djamei
Host Institution (HI) GREGOR MENDEL INSTITUT FUR MOLEKULARE PFLANZENBIOLOGIE GMBH
Call Details Starting Grant (StG), LS2, ERC-2013-StG
Summary "Our existence as human beings is based on plants and their products. Worldwide, crops are threatened by pests including biotrophic fungi. Therefore, it is of vital interest to develop new strategies to reduce crop losses and to improve crop plants for the growing world population. Biotrophic plant pathogens employ small secreted molecules, so-called effectors, to overcome plant defence systems and to establish biotrophy. The rapid increase in available genome sequences of biotrophic pathogens and in transcriptomic datasets of their biotrophic stages allow us to identify putative secreted proteinaceous effectors by bioinformatic means. However, our insight into the functions of these effectors is still very limited. In this proposal, the PI´s extensive experience on both the plant host side and the fungal pathogen side of the biotrophic interaction is exploited to develop a workflow for functional, partially robotic-based screens to fill this gap. The combination of screen-deduced functional information with the analysis of effector localisation and specific host interactors will provide the basis for formulating starting hypotheses of effector function. These will then be tested in individual case studies, employing the well established Ustilago maydis-Zea mays as well as the new Ustilago bromivora-Brachypodium distachyon model systems. The project will be conducted at the Max Planck Institute (MPI) for Terrestrial Microbiology in a highly stimulating scientific environment. Linking the dramatic morphological changes and underlying molecular events during biotrophy on the host side to the action of subsets or even single effector proteins will allow the creation of a synthetic effectome. The deep functional understanding of the manipulative toolbox of biotrophs has the potential to facilitate transgenic crop development and will open a new era in the development of sustainable antifungal plant protection strategies."
Summary
"Our existence as human beings is based on plants and their products. Worldwide, crops are threatened by pests including biotrophic fungi. Therefore, it is of vital interest to develop new strategies to reduce crop losses and to improve crop plants for the growing world population. Biotrophic plant pathogens employ small secreted molecules, so-called effectors, to overcome plant defence systems and to establish biotrophy. The rapid increase in available genome sequences of biotrophic pathogens and in transcriptomic datasets of their biotrophic stages allow us to identify putative secreted proteinaceous effectors by bioinformatic means. However, our insight into the functions of these effectors is still very limited. In this proposal, the PI´s extensive experience on both the plant host side and the fungal pathogen side of the biotrophic interaction is exploited to develop a workflow for functional, partially robotic-based screens to fill this gap. The combination of screen-deduced functional information with the analysis of effector localisation and specific host interactors will provide the basis for formulating starting hypotheses of effector function. These will then be tested in individual case studies, employing the well established Ustilago maydis-Zea mays as well as the new Ustilago bromivora-Brachypodium distachyon model systems. The project will be conducted at the Max Planck Institute (MPI) for Terrestrial Microbiology in a highly stimulating scientific environment. Linking the dramatic morphological changes and underlying molecular events during biotrophy on the host side to the action of subsets or even single effector proteins will allow the creation of a synthetic effectome. The deep functional understanding of the manipulative toolbox of biotrophs has the potential to facilitate transgenic crop development and will open a new era in the development of sustainable antifungal plant protection strategies."
Max ERC Funding
1 446 316 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym EINME
Project Systematic investigation of epistasis in molecular evolution
Researcher (PI) Fyodor Kondrashov
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGYAUSTRIA
Call Details Starting Grant (StG), LS2, ERC-2013-StG
Summary Why does a mutation have a deleterious effect when it occurs in one species but shows no apparent consequences on the phenotype when it occurs in another species? What are some of possible explanations on the molecular basis of this phenomenon? Are the computational predictions of the extent of this phenomenon in nature accurate? The present project aims to take a swing at answering, at least partially, these basic questions of epistasis in molecular evolution. Within our work we plan to address these issues using computational approaches, systematic fitness assays of engineered orthologous genotypes and experimental functional assays of specific cases of epistasis identified by evolutionary analysis. By tackling these goals and utilising this array of approaches the projects aims to create a synthesis between theory and experimentation under the confines of a single laboratory that will allow us to study this phenomenon in a systematic fashion on the interface of different fields and methodologies.
Summary
Why does a mutation have a deleterious effect when it occurs in one species but shows no apparent consequences on the phenotype when it occurs in another species? What are some of possible explanations on the molecular basis of this phenomenon? Are the computational predictions of the extent of this phenomenon in nature accurate? The present project aims to take a swing at answering, at least partially, these basic questions of epistasis in molecular evolution. Within our work we plan to address these issues using computational approaches, systematic fitness assays of engineered orthologous genotypes and experimental functional assays of specific cases of epistasis identified by evolutionary analysis. By tackling these goals and utilising this array of approaches the projects aims to create a synthesis between theory and experimentation under the confines of a single laboratory that will allow us to study this phenomenon in a systematic fashion on the interface of different fields and methodologies.
Max ERC Funding
1 461 576 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym MAXMAP
Project Developing maximum-resolution genotype-phenotype maps using whole-genome polymorphism data
Researcher (PI) Lars Magnus Henrik Nordborg
Host Institution (HI) GREGOR MENDEL INSTITUT FUR MOLEKULARE PFLANZENBIOLOGIE GMBH
Call Details Advanced Grant (AdG), LS2, ERC-2010-AdG_20100317
Summary Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases, genome-wide association studies (GWAS) have, owing to advances in genotyping and sequencing technology, become an obvious general approach for studying the genetics of natural variation. They are particularly useful when inbred lines are available because once these lines have been genotyped they can be phenotyped multiple times, making it possible (as well as extremely cost-effective) to study many different traits in many different environments, while replicating the phenotypic measurements to reduce environmental noise. Here we propose to continue our groundbreaking GWAS work in the model plant Arabidopsis thaliana. We will explore the limits of the approach, moving beyond marker-trait linkage disequilibrium to full sequence information. We will carry out GWAS of important life-history traits using over 1000 inbred A. thaliana lines for which nearly complete sequence information is available. The GWAS will be complemented by linkage mapping in F2 crosses to eliminate confounding linkage disequilibrium, associations will be verified experimentally, and confirmed causal polymorphisms will be added to the model in an iterative manner in order to create an increasingly refined genotype-phenotype map.
Summary
Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases, genome-wide association studies (GWAS) have, owing to advances in genotyping and sequencing technology, become an obvious general approach for studying the genetics of natural variation. They are particularly useful when inbred lines are available because once these lines have been genotyped they can be phenotyped multiple times, making it possible (as well as extremely cost-effective) to study many different traits in many different environments, while replicating the phenotypic measurements to reduce environmental noise. Here we propose to continue our groundbreaking GWAS work in the model plant Arabidopsis thaliana. We will explore the limits of the approach, moving beyond marker-trait linkage disequilibrium to full sequence information. We will carry out GWAS of important life-history traits using over 1000 inbred A. thaliana lines for which nearly complete sequence information is available. The GWAS will be complemented by linkage mapping in F2 crosses to eliminate confounding linkage disequilibrium, associations will be verified experimentally, and confirmed causal polymorphisms will be added to the model in an iterative manner in order to create an increasingly refined genotype-phenotype map.
Max ERC Funding
2 183 956 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
Project acronym OVERMODE
Project Origins of the Vernacular Mode. Regional Identities and European Networks in Late Medieval Europe
Researcher (PI) Pavlína Rychterová
Host Institution (HI) OESTERREICHISCHE AKADEMIE DER WISSENSCHAFTEN
Call Details Starting Grant (StG), SH6, ERC-2010-StG_20091209
Summary Based on comparative studies and contextualisations of European vernacular religious literatures, this project aims at new insights about the dynamics of regional ( vernacular ) identity formation in the 14th and 15th centuries. The investigation will focus on intellectual elites linked in close, supra-regional networks, who gradually introduced the vernacular mode in the dominant theological discourse; at the same time, they increased the symbolical charge of the vernacular languages. The core period studied in the project will be the second half of the 14th century, a period in which new forms of institutionalisation and discursive orientation of ecclesiastic and lay powers began to take shape, and directions were taken that should prove decisive for further development. At the time, Prague was the political and intellectual centre of the Holy Roman Empire, but its international impact is grossly understudied. The project will therefore mainly deal with the rich and little-known production of Czech religious literature. It sets out to reconstruct the personal networks engaged in the creation, translation and propagation of vernacular religious literature, and in the formation of textual communities and cultural identities at the treshold from Latin to the vernaculars.
Summary
Based on comparative studies and contextualisations of European vernacular religious literatures, this project aims at new insights about the dynamics of regional ( vernacular ) identity formation in the 14th and 15th centuries. The investigation will focus on intellectual elites linked in close, supra-regional networks, who gradually introduced the vernacular mode in the dominant theological discourse; at the same time, they increased the symbolical charge of the vernacular languages. The core period studied in the project will be the second half of the 14th century, a period in which new forms of institutionalisation and discursive orientation of ecclesiastic and lay powers began to take shape, and directions were taken that should prove decisive for further development. At the time, Prague was the political and intellectual centre of the Holy Roman Empire, but its international impact is grossly understudied. The project will therefore mainly deal with the rich and little-known production of Czech religious literature. It sets out to reconstruct the personal networks engaged in the creation, translation and propagation of vernacular religious literature, and in the formation of textual communities and cultural identities at the treshold from Latin to the vernaculars.
Max ERC Funding
999 926 €
Duration
Start date: 2011-04-01, End date: 2017-03-31
Project acronym PREHISTORIC ANATOLIA
Project From Sedentism to Proto-Urban Societies in Western Anatolia
Researcher (PI) Barbara Horejs
Host Institution (HI) OESTERREICHISCHE AKADEMIE DER WISSENSCHAFTEN
Call Details Starting Grant (StG), SH6, ERC-2010-StG_20091209
Summary Prehistoric archaeology in western Anatolia has been poorly pursued since the beginning of excavations in this area in the 19th century. Especially the central coast between Pergamon and Ephesos represents a terra incognita in most prehistoric periods of humankind.
The project focuses mainly on two distinctive chronological and cultural horizons the period of the first permanent settlements (sedentism) in Neolithic and the development to proto-urban centres in Early Bronze Age period. Combining both huge research topics in one project would enable a broad spectrum of cultural modelling, based upon multidisciplinary diachronic and comparative studies concerning changing societies in a changing environment from the 7th to 3rd millennium BC.
New archaeological excavations as well as environmental surveys in different micro-regions (Pergamon and Ephesos) are the essential methods to produce modern documented data that will be analysed with a broad multidisciplinary and international team of scientists and students. Besides archaeology, those disciplines are geophysics, paleogeography, metallurgy, inorganic chemistry, petrography/mineralogy, geology, zoology, botany, anthracology, organic chemistry, physics and anthropology.
To achieve an integrated picture and to concentrate the broad spectrum of studies a focus on the following three research topics is proposed: 1. Archaeological Periods and Definitions of Cultures 2. Societies in Changing Environments 3. Communication, Exchange and Interregional Relationships. The applicant has already performed investigations in these highly promising regions and could thereby successfully demonstrate a great gain in knowledge of basic cultural developments of humankind in prehistory.
Summary
Prehistoric archaeology in western Anatolia has been poorly pursued since the beginning of excavations in this area in the 19th century. Especially the central coast between Pergamon and Ephesos represents a terra incognita in most prehistoric periods of humankind.
The project focuses mainly on two distinctive chronological and cultural horizons the period of the first permanent settlements (sedentism) in Neolithic and the development to proto-urban centres in Early Bronze Age period. Combining both huge research topics in one project would enable a broad spectrum of cultural modelling, based upon multidisciplinary diachronic and comparative studies concerning changing societies in a changing environment from the 7th to 3rd millennium BC.
New archaeological excavations as well as environmental surveys in different micro-regions (Pergamon and Ephesos) are the essential methods to produce modern documented data that will be analysed with a broad multidisciplinary and international team of scientists and students. Besides archaeology, those disciplines are geophysics, paleogeography, metallurgy, inorganic chemistry, petrography/mineralogy, geology, zoology, botany, anthracology, organic chemistry, physics and anthropology.
To achieve an integrated picture and to concentrate the broad spectrum of studies a focus on the following three research topics is proposed: 1. Archaeological Periods and Definitions of Cultures 2. Societies in Changing Environments 3. Communication, Exchange and Interregional Relationships. The applicant has already performed investigations in these highly promising regions and could thereby successfully demonstrate a great gain in knowledge of basic cultural developments of humankind in prehistory.
Max ERC Funding
1 256 428 €
Duration
Start date: 2011-07-01, End date: 2016-06-30
Project acronym SCIRE
Project Social Cohesion, Identity and Religion in Europe, 400-1200
Researcher (PI) Walter Pohl
Host Institution (HI) UNIVERSITAT WIEN
Call Details Advanced Grant (AdG), SH6, ERC-2010-AdG_20100407
Summary The period between 400 and 1200 AD saw the emergence of new fundamental modes of identification in Europe. Firstly, strong religious identities took shape and became hegemonial over vast regions where Christian communities developed. And secondly, new kingdoms with ethnic denominations were formed, and the Roman empire gave way to a pluralistic political landscape. Most ethnic designations for medieval and modern states in fact go back to that period. Both processes, not least through their interaction, created new forms of social cohesion, but also of conflict, and had a deep impact on European history up to this day that has not been sufficiently understood yet. Universal religion and ethnic/national particularism have always been regarded as opposite principles. But that is only part of the picture, and the proposed project is intended to look systematically at the ways in which religious and ethnic identities interacted, both as forms of discourse and as social practices.
In studying the Early Middle Ages, the project addresses a period that has been neglected in debates about ethnicity and the rise of the nation. By choosing a long-term perspective, it attempts to historicize ethnicity and religion. Specifically, the project will concentrate on the ways in which the Bible inspired new discourses of identity and ethnicity, and in which the formation of Christian communities could enhance ethnic and political cohesion. Important political, affective and cognitive resources for the political role of ethnicity in European history were created in Late Antiquity and the Early and High Middle Ages, c. 400–1200 AD. They provided a potential that could be used at different stages in European history, not least, in the development of the modern nation.
Summary
The period between 400 and 1200 AD saw the emergence of new fundamental modes of identification in Europe. Firstly, strong religious identities took shape and became hegemonial over vast regions where Christian communities developed. And secondly, new kingdoms with ethnic denominations were formed, and the Roman empire gave way to a pluralistic political landscape. Most ethnic designations for medieval and modern states in fact go back to that period. Both processes, not least through their interaction, created new forms of social cohesion, but also of conflict, and had a deep impact on European history up to this day that has not been sufficiently understood yet. Universal religion and ethnic/national particularism have always been regarded as opposite principles. But that is only part of the picture, and the proposed project is intended to look systematically at the ways in which religious and ethnic identities interacted, both as forms of discourse and as social practices.
In studying the Early Middle Ages, the project addresses a period that has been neglected in debates about ethnicity and the rise of the nation. By choosing a long-term perspective, it attempts to historicize ethnicity and religion. Specifically, the project will concentrate on the ways in which the Bible inspired new discourses of identity and ethnicity, and in which the formation of Christian communities could enhance ethnic and political cohesion. Important political, affective and cognitive resources for the political role of ethnicity in European history were created in Late Antiquity and the Early and High Middle Ages, c. 400–1200 AD. They provided a potential that could be used at different stages in European history, not least, in the development of the modern nation.
Max ERC Funding
1 983 000 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
