Project acronym CHAPARDYN
Project Chaos in Parabolic Dynamics: Mixing, Rigidity, Spectra
Researcher (PI) Corinna Ulcigrai
Host Institution (HI) UNIVERSITY OF BRISTOL
Call Details Starting Grant (StG), PE1, ERC-2013-StG
Summary "The theme of the proposal is the mathematical investigation of chaos (in particular ergodic and spectral properties) in parabolic dynamics, via analytic, geometric and probabilistic techniques. Parabolic dynamical systems are mathematical models of the many phenomena which display a ""slow"" form of chaotic evolution, in the sense that nearby trajectories diverge polynomially in time. In contrast with the hyperbolic case and with the elliptic case, there is no general theory which describes parabolic dynamical systems. Only few classical examples are well understood.
The research plan aims at bridging this gap, by studying new classes of parabolic systems and unexplored properties of classical ones. More precisely, I propose to study parabolic flows beyond the algebraic set-up and infinite measure-preserving parabolic systems, both of which are very virgin fields of research, and to attack open conjectures and questions on fine chaotic properties, such as spectra and rigidity, for area-preserving flows. Moreover, connections between parabolic dynamics and respectively number theory, mathematical physics and probability will be explored. g New techniques, stemming from some recent breakthroughs in Teichmueller dynamics, spectral theory and infinite ergodic theory, will be developed.
The proposed research will bring our knowledge significantly beyond the current state-of-the art, both in breadth and depth and will identify common features and mechanisms for chaos in parabolic systems. Understanding similar features and common geometric mechanisms responsible for mixing, rigidity and spectral properties of parabolic systems will provide important insight towards an universal theory of parabolic dynamics."
Summary
"The theme of the proposal is the mathematical investigation of chaos (in particular ergodic and spectral properties) in parabolic dynamics, via analytic, geometric and probabilistic techniques. Parabolic dynamical systems are mathematical models of the many phenomena which display a ""slow"" form of chaotic evolution, in the sense that nearby trajectories diverge polynomially in time. In contrast with the hyperbolic case and with the elliptic case, there is no general theory which describes parabolic dynamical systems. Only few classical examples are well understood.
The research plan aims at bridging this gap, by studying new classes of parabolic systems and unexplored properties of classical ones. More precisely, I propose to study parabolic flows beyond the algebraic set-up and infinite measure-preserving parabolic systems, both of which are very virgin fields of research, and to attack open conjectures and questions on fine chaotic properties, such as spectra and rigidity, for area-preserving flows. Moreover, connections between parabolic dynamics and respectively number theory, mathematical physics and probability will be explored. g New techniques, stemming from some recent breakthroughs in Teichmueller dynamics, spectral theory and infinite ergodic theory, will be developed.
The proposed research will bring our knowledge significantly beyond the current state-of-the art, both in breadth and depth and will identify common features and mechanisms for chaos in parabolic systems. Understanding similar features and common geometric mechanisms responsible for mixing, rigidity and spectral properties of parabolic systems will provide important insight towards an universal theory of parabolic dynamics."
Max ERC Funding
1 193 534 €
Duration
Start date: 2014-01-01, End date: 2019-08-31
Project acronym COMPAT
Project Complex Patterns for Strongly Interacting Dynamical Systems
Researcher (PI) Susanna Terracini
Host Institution (HI) UNIVERSITA DEGLI STUDI DI TORINO
Call Details Advanced Grant (AdG), PE1, ERC-2013-ADG
Summary This project focuses on nontrivial solutions of systems of differential equations characterized by strongly nonlinear interactions. We are interested in the effect of the nonlinearities on the emergence of non trivial self-organized structures. Such patterns correspond to selected solutions of the differential system possessing special symmetries or shadowing particular shapes. We want to understand, from the
mathematical point of view, what are the main mechanisms involved in the aggregation process in terms of the global variational structure of the problem. Following this common thread, we deal with both with the classical N-body problem of Celestial Mechanics, where interactions feature attractive singularities, and competition-diffusion systems, where pattern formation is driven by strongly repulsive forces. More
precisely, we are interested in periodic and bounded solutions, parabolic trajectories with the final intent to build complex motions and possibly obtain the symbolic dynamics for the general N–body problem. On the other hand, we deal with elliptic, parabolic and hyperbolic systems of differential equations with strongly competing interaction terms, modeling both the dynamics of competing populations (Lotka-
Volterra systems) and other interesting physical phenomena, among which the phase segregation of solitary waves of Gross-Pitaevskii systems arising in the study of multicomponent Bose-Einstein condensates. In particular, we will study existence, multiplicity and asymptotic expansions of solutions when the competition parameter tends to infinity. We shall be concerned with optimal partition problems
related to linear and nonlinear eigenvalues
Summary
This project focuses on nontrivial solutions of systems of differential equations characterized by strongly nonlinear interactions. We are interested in the effect of the nonlinearities on the emergence of non trivial self-organized structures. Such patterns correspond to selected solutions of the differential system possessing special symmetries or shadowing particular shapes. We want to understand, from the
mathematical point of view, what are the main mechanisms involved in the aggregation process in terms of the global variational structure of the problem. Following this common thread, we deal with both with the classical N-body problem of Celestial Mechanics, where interactions feature attractive singularities, and competition-diffusion systems, where pattern formation is driven by strongly repulsive forces. More
precisely, we are interested in periodic and bounded solutions, parabolic trajectories with the final intent to build complex motions and possibly obtain the symbolic dynamics for the general N–body problem. On the other hand, we deal with elliptic, parabolic and hyperbolic systems of differential equations with strongly competing interaction terms, modeling both the dynamics of competing populations (Lotka-
Volterra systems) and other interesting physical phenomena, among which the phase segregation of solitary waves of Gross-Pitaevskii systems arising in the study of multicomponent Bose-Einstein condensates. In particular, we will study existence, multiplicity and asymptotic expansions of solutions when the competition parameter tends to infinity. We shall be concerned with optimal partition problems
related to linear and nonlinear eigenvalues
Max ERC Funding
1 346 145 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym Critical
Project Behaviour near criticality
Researcher (PI) Martin Hairer
Host Institution (HI) THE UNIVERSITY OF WARWICK
Call Details Consolidator Grant (CoG), PE1, ERC-2013-CoG
Summary "One of the main challenges of modern mathematical physics is to understand the behaviour of systems at or near criticality. In a number of cases, one can argue heuristically that this behaviour should be described by a nonlinear stochastic partial differential equation. Some examples of systems of interest are models of phase coexistence near the critical temperature, one-dimensional interface growth models, and models of absorption of a diffusing particle by random impurities. Unfortunately, the equations arising in all of these contexts are mathematically ill-posed. This is to the extent that they defeat not only ""standard"" stochastic PDE techniques (as developed by Da Prato / Zabczyk / Röckner / Walsh / Krylov / etc), but also more recent approaches based on Wick renormalisation of nonlinearities (Da Prato / Debussche / etc).
Over the past year or so, I have been developing a theory of regularity structures that allows to give a rigorous mathematical interpretation to such equations, which therefore allows to build the mathematical objects conjectured to describe the abovementioned systems near criticality. The aim of the proposal is to study the convergence of a variety of concrete microscopic models to these limiting objects. The main fundamental mathematical tools to be developed in this endeavour are a discrete analogue to the theory of regularity structures, as well as a number of nonlinear invariance principles.
If successful, the project will yield unique insight in the large-scale behaviour of a number of physically relevant systems in regimes where both nonlinear effects and random fluctuations compete with equal strength."
Summary
"One of the main challenges of modern mathematical physics is to understand the behaviour of systems at or near criticality. In a number of cases, one can argue heuristically that this behaviour should be described by a nonlinear stochastic partial differential equation. Some examples of systems of interest are models of phase coexistence near the critical temperature, one-dimensional interface growth models, and models of absorption of a diffusing particle by random impurities. Unfortunately, the equations arising in all of these contexts are mathematically ill-posed. This is to the extent that they defeat not only ""standard"" stochastic PDE techniques (as developed by Da Prato / Zabczyk / Röckner / Walsh / Krylov / etc), but also more recent approaches based on Wick renormalisation of nonlinearities (Da Prato / Debussche / etc).
Over the past year or so, I have been developing a theory of regularity structures that allows to give a rigorous mathematical interpretation to such equations, which therefore allows to build the mathematical objects conjectured to describe the abovementioned systems near criticality. The aim of the proposal is to study the convergence of a variety of concrete microscopic models to these limiting objects. The main fundamental mathematical tools to be developed in this endeavour are a discrete analogue to the theory of regularity structures, as well as a number of nonlinear invariance principles.
If successful, the project will yield unique insight in the large-scale behaviour of a number of physically relevant systems in regimes where both nonlinear effects and random fluctuations compete with equal strength."
Max ERC Funding
1 526 234 €
Duration
Start date: 2014-09-01, End date: 2019-08-31
Project acronym DNAMEREP
Project The role of essential DNA metabolism genes in vertebrate chromosome replication
Researcher (PI) Vincenzo Costanzo
Host Institution (HI) IFOM FONDAZIONE ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE
Call Details Consolidator Grant (CoG), LS1, ERC-2013-CoG
Summary "Faithful chromosomal DNA replication is essential to maintain genome stability. A number of DNA metabolism genes are involved at different levels in DNA replication. These factors are thought to facilitate the establishment of replication origins, assist the replication of chromatin regions with repetitive DNA, coordinate the repair of DNA molecules resulting from aberrant DNA replication events or protect replication forks in the presence of DNA lesions that impair their progression. Some DNA metabolism genes are present mainly in higher eukaryotes, suggesting the existence of more complex repair and replication mechanisms in organisms with complex genomes. The impact on cell survival of many DNA metabolism genes has so far precluded in depth molecular analysis. The use of cell free extracts able to recapitulate cell cycle events might help overcoming survival issues and facilitate these studies. The Xenopus laevis egg cell free extract represents an ideal system to study replication-associated functions of essential genes in vertebrate organisms. We will take advantage of this system together with innovative imaging and proteomic based experimental approaches that we are currently developing to characterize the molecular function of some essential DNA metabolism genes. In particular, we will characterize DNA metabolism genes involved in the assembly and distribution of replication origins in vertebrate cells, elucidate molecular mechanisms underlying the role of essential homologous recombination and fork protection proteins in chromosomal DNA replication, and finally identify and characterize factors required for faithful replication of specific vertebrate genomic regions.
The results of these studies will provide groundbreaking information on several aspects of vertebrate genome metabolism and will allow long-awaited understanding of the function of a number of vertebrate essential DNA metabolism genes involved in the duplication of large and complex genomes."
Summary
"Faithful chromosomal DNA replication is essential to maintain genome stability. A number of DNA metabolism genes are involved at different levels in DNA replication. These factors are thought to facilitate the establishment of replication origins, assist the replication of chromatin regions with repetitive DNA, coordinate the repair of DNA molecules resulting from aberrant DNA replication events or protect replication forks in the presence of DNA lesions that impair their progression. Some DNA metabolism genes are present mainly in higher eukaryotes, suggesting the existence of more complex repair and replication mechanisms in organisms with complex genomes. The impact on cell survival of many DNA metabolism genes has so far precluded in depth molecular analysis. The use of cell free extracts able to recapitulate cell cycle events might help overcoming survival issues and facilitate these studies. The Xenopus laevis egg cell free extract represents an ideal system to study replication-associated functions of essential genes in vertebrate organisms. We will take advantage of this system together with innovative imaging and proteomic based experimental approaches that we are currently developing to characterize the molecular function of some essential DNA metabolism genes. In particular, we will characterize DNA metabolism genes involved in the assembly and distribution of replication origins in vertebrate cells, elucidate molecular mechanisms underlying the role of essential homologous recombination and fork protection proteins in chromosomal DNA replication, and finally identify and characterize factors required for faithful replication of specific vertebrate genomic regions.
The results of these studies will provide groundbreaking information on several aspects of vertebrate genome metabolism and will allow long-awaited understanding of the function of a number of vertebrate essential DNA metabolism genes involved in the duplication of large and complex genomes."
Max ERC Funding
1 999 800 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym EMPSI
Project Receptors, Channels and Transporters:
Development and Application of Novel Technologies for Structure Determination
Researcher (PI) Christopher Gordon Tate
Host Institution (HI) MEDICAL RESEARCH COUNCIL
Call Details Advanced Grant (AdG), LS1, ERC-2013-ADG
Summary Structure determination of G protein-coupled receptors (GPCRs) has been exceedingly successful over the last 5 years due to the development of complimentary generic methodologies that will now allow the structure determination of virtually any GPCR. However, these technologies address only two aspects of the process, namely the stability of the receptors during purification and the ability to form well-diffracting crystals. The strategies also apply only to GPCRs and not transporters or ion channels. The recent successes have been of GPCRs that are expressed in either yeasts or in insect cells using the baculovirus expression system, but many membrane proteins are expressed poorly in these systems or may be expressed in a misfolded non-functional form. A second issue with the future structure determination of GPCRs is the lack of generic technologies to allow the crystallisation of arrestin-GPCR and G protein-GPCR complexes. Although one G protein GPCR complex has been crystallised this was exceedingly diffciult and resulted in poor resolution of the GPCR component of the complex. We believe that it is possible to thermostabilise both arrestin and heterotrimeric G proteins, which will allow a simplified strategy for the crystallisation and structure determination of GPCR complexes. This is based on the development of the strategy of conformational thermostabilisation of GPCRs developed in our lab that has resulted in the structure determination of 3 different GPCRs bound to either antagonists, partial agonists, full agonists and/or biased agonists.
The aims are:
1. The development of generic methodology for the production of eukaryotic membrane proteins in mammalian cells.
2. The development of a thermostable functional arrestin mutant
3. Structures of β1-adrenoceptor, adenosine A2A receptor and angiotensin receptor bound to a G protein and arrestin
4. Understanding the role of each amino acid residue in the activation process of GPCRs through saturation mutagenes
Summary
Structure determination of G protein-coupled receptors (GPCRs) has been exceedingly successful over the last 5 years due to the development of complimentary generic methodologies that will now allow the structure determination of virtually any GPCR. However, these technologies address only two aspects of the process, namely the stability of the receptors during purification and the ability to form well-diffracting crystals. The strategies also apply only to GPCRs and not transporters or ion channels. The recent successes have been of GPCRs that are expressed in either yeasts or in insect cells using the baculovirus expression system, but many membrane proteins are expressed poorly in these systems or may be expressed in a misfolded non-functional form. A second issue with the future structure determination of GPCRs is the lack of generic technologies to allow the crystallisation of arrestin-GPCR and G protein-GPCR complexes. Although one G protein GPCR complex has been crystallised this was exceedingly diffciult and resulted in poor resolution of the GPCR component of the complex. We believe that it is possible to thermostabilise both arrestin and heterotrimeric G proteins, which will allow a simplified strategy for the crystallisation and structure determination of GPCR complexes. This is based on the development of the strategy of conformational thermostabilisation of GPCRs developed in our lab that has resulted in the structure determination of 3 different GPCRs bound to either antagonists, partial agonists, full agonists and/or biased agonists.
The aims are:
1. The development of generic methodology for the production of eukaryotic membrane proteins in mammalian cells.
2. The development of a thermostable functional arrestin mutant
3. Structures of β1-adrenoceptor, adenosine A2A receptor and angiotensin receptor bound to a G protein and arrestin
4. Understanding the role of each amino acid residue in the activation process of GPCRs through saturation mutagenes
Max ERC Funding
2 378 162 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym HIGEOM
Project Highly accurate Isogeometric Method
Researcher (PI) Giancarlo Sangalli
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PAVIA
Call Details Consolidator Grant (CoG), PE1, ERC-2013-CoG
Summary "Partial Differential Equations (PDEs) are widely used in science and engineering simulations, often in tight connection with Computer Aided Design (CAD). The Finite Element Method (FEM) is one of the most popular technique for the discretization of PDEs. The IsoGeometric Method (IGM), proposed in 2005 by T.J.R. Hughes et al., aims at improving the interoperability between CAD and FEMs. This is achieved by adopting the CAD mathematical primitives, i.e. Splines and Non-Uniform Rational B-Splines (NURBS), both for geometry and unknown fields representation. The IGM has gained an incredible momentum especially in the engineering community. The use of high-degree, highly smooth NURBS is extremely successful and the IGM outperforms the FEM in most academic benchmarks.
However, we are far from having a satisfactory mathematical understanding of the IGM and, even more importantly, from exploiting its full potential. Until now, the IGM theory and practice have been deeply influenced by finite element analysis. For example, the IGM is implemented resorting to a FEM code design, which is very inefficient for high-degree and high-smoothness NURBS. This has made possible a fast spreading of the IGM, but also limited it to quadratic or cubic NURBS in complex simulations.
The use of higher degree IGM for real-world applications asks for new tools allowing for the efficient construction and solution of the linear system, time integration, flexible local mesh refinement, and so on. These questions need to be approached beyond the FEM framework. This is possible only on solid mathematical grounds, on a new theory of splines and NURBS able to comply with the needs of the IGM.
This project will provide the crucial knowledge and will re-design the IGM to make it a superior, highly accurate and stable methodology, having a significant impact in the field of numerical simulation of PDEs, particularly when accuracy is essential both in geometry and fields representation."
Summary
"Partial Differential Equations (PDEs) are widely used in science and engineering simulations, often in tight connection with Computer Aided Design (CAD). The Finite Element Method (FEM) is one of the most popular technique for the discretization of PDEs. The IsoGeometric Method (IGM), proposed in 2005 by T.J.R. Hughes et al., aims at improving the interoperability between CAD and FEMs. This is achieved by adopting the CAD mathematical primitives, i.e. Splines and Non-Uniform Rational B-Splines (NURBS), both for geometry and unknown fields representation. The IGM has gained an incredible momentum especially in the engineering community. The use of high-degree, highly smooth NURBS is extremely successful and the IGM outperforms the FEM in most academic benchmarks.
However, we are far from having a satisfactory mathematical understanding of the IGM and, even more importantly, from exploiting its full potential. Until now, the IGM theory and practice have been deeply influenced by finite element analysis. For example, the IGM is implemented resorting to a FEM code design, which is very inefficient for high-degree and high-smoothness NURBS. This has made possible a fast spreading of the IGM, but also limited it to quadratic or cubic NURBS in complex simulations.
The use of higher degree IGM for real-world applications asks for new tools allowing for the efficient construction and solution of the linear system, time integration, flexible local mesh refinement, and so on. These questions need to be approached beyond the FEM framework. This is possible only on solid mathematical grounds, on a new theory of splines and NURBS able to comply with the needs of the IGM.
This project will provide the crucial knowledge and will re-design the IGM to make it a superior, highly accurate and stable methodology, having a significant impact in the field of numerical simulation of PDEs, particularly when accuracy is essential both in geometry and fields representation."
Max ERC Funding
928 188 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym MUNCODD
Project Role of long non coding RNA in muscle differentiation and disease
Researcher (PI) Irene Bozzoni
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA
Call Details Advanced Grant (AdG), LS1, ERC-2013-ADG
Summary "The field of interest applies to the study of muscle differentiation and disease. The main objective of this project is to deepen our knowledge on the molecular networks controlling normal muscle differentiation, and to identify their alteration in pathology. The state of art in this field is thoroughly advanced since well-established master regulators (transcriptional factors and miRNAs) have been deeply characterized and integrated in regulatory circuitries controlling muscle development and differentiation. However, recent discoveries point to the hierarchically relevant role of a previously disregarded class of transcripts, named long non-coding RNAs (lncRNAs), in the control of gene expression.
Therefore, a major objective of this project is to re-evaluate and re-design established molecular circuitries known to control muscle differentiation in the light of the contribution of this complex class of transcripts. In more general terms, the project will shed light on the biogenesis and function of lncRNAs and how they contribute to cellular and organismal biology.
This is a very new and innovative field of research that holds promise for a significant increase in our understanding of basic molecular processes and should constitute a vast and largely unexplored territory for the development of novel therapeutics and diagnostics."
Summary
"The field of interest applies to the study of muscle differentiation and disease. The main objective of this project is to deepen our knowledge on the molecular networks controlling normal muscle differentiation, and to identify their alteration in pathology. The state of art in this field is thoroughly advanced since well-established master regulators (transcriptional factors and miRNAs) have been deeply characterized and integrated in regulatory circuitries controlling muscle development and differentiation. However, recent discoveries point to the hierarchically relevant role of a previously disregarded class of transcripts, named long non-coding RNAs (lncRNAs), in the control of gene expression.
Therefore, a major objective of this project is to re-evaluate and re-design established molecular circuitries known to control muscle differentiation in the light of the contribution of this complex class of transcripts. In more general terms, the project will shed light on the biogenesis and function of lncRNAs and how they contribute to cellular and organismal biology.
This is a very new and innovative field of research that holds promise for a significant increase in our understanding of basic molecular processes and should constitute a vast and largely unexplored territory for the development of novel therapeutics and diagnostics."
Max ERC Funding
2 000 000 €
Duration
Start date: 2014-07-01, End date: 2019-06-30
Project acronym MUSYX
Project Multiscale Simulation of Crystal Defects
Researcher (PI) Christoph Ortner
Host Institution (HI) THE UNIVERSITY OF WARWICK
Call Details Starting Grant (StG), PE1, ERC-2013-StG
Summary "The MUSYX project will develop a rigorous numerical analysis framework for assessing the accuracy of multiscale methods for simulating the dynamics of crystalline defects. The core focus of the research will be the analysis of approximation errors of atomistic-to-continuum (a/c) coupling methods and related multiscale schemes. The rigorous mathematical foundations, which will be the outcome of this work, will also lead to the construction of more robust and more efficient numerical algorithms.
The research will be undertaken within four distinct but closely related themes: Theme A: quasistatic evolutions up to and including bifurcation points (defect nucleation and evolution); Theme B: Transition paths, saddles, and transition rates between local minima (defect nucleation and diffusion at finite temperature); Theme C: Computation of defect formation energies within the framework of equilibrium statistical mechanics; Theme D: Fully dynamic problems. The four themes are connected through the focus on crystal defects and model interfaces (e.g., atomistic/continuum).
Themes A and B build on and significantly extend the theory of a/c coupling pioneered by the PI, which combines classical techniques of numerical analysis (consistency, stability) with modern concepts of multiscale and atomistic modeling. Theme C aims to develop an analogous theory for multiscale free energy calculations (precisely, defect formation energies). Theme D approaches the analysis of a fully dynamic multiscale scheme by analyzing its qualitative statistical properties."
Summary
"The MUSYX project will develop a rigorous numerical analysis framework for assessing the accuracy of multiscale methods for simulating the dynamics of crystalline defects. The core focus of the research will be the analysis of approximation errors of atomistic-to-continuum (a/c) coupling methods and related multiscale schemes. The rigorous mathematical foundations, which will be the outcome of this work, will also lead to the construction of more robust and more efficient numerical algorithms.
The research will be undertaken within four distinct but closely related themes: Theme A: quasistatic evolutions up to and including bifurcation points (defect nucleation and evolution); Theme B: Transition paths, saddles, and transition rates between local minima (defect nucleation and diffusion at finite temperature); Theme C: Computation of defect formation energies within the framework of equilibrium statistical mechanics; Theme D: Fully dynamic problems. The four themes are connected through the focus on crystal defects and model interfaces (e.g., atomistic/continuum).
Themes A and B build on and significantly extend the theory of a/c coupling pioneered by the PI, which combines classical techniques of numerical analysis (consistency, stability) with modern concepts of multiscale and atomistic modeling. Theme C aims to develop an analogous theory for multiscale free energy calculations (precisely, defect formation energies). Theme D approaches the analysis of a fully dynamic multiscale scheme by analyzing its qualitative statistical properties."
Max ERC Funding
1 111 793 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym NanoScope
Project Optical imaging of nanoscopic dynamics and potentials
Researcher (PI) Philipp Kukura
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), LS1, ERC-2013-StG
Summary I propose to develop and apply a novel approach to optical microscopy to enable the direct visualization and study of dynamics on the nanoscale in biological and condensed matter physics. Given the speed with which nanoscopic objects move at ambient condition, this requires simultaneously very fast (ms) and precise (nm) imaging. The challenge is to avoid excessive perturbation of the system and enable imaging in biologically compatible environments without compromising imaging performance by pushing interferometric scattering to its theoretical limits.
Using these advanced capabilities, I will study the dynamics and thereby the structure-function relationships in three fundamental systems that are currently not captured by even the most advanced biophysical approaches. These include: (1) the flexibility of DNA on short length scales, (2) diffusion in artificial and cellular membranes and (3) the three-dimensional power stroke of molecular motors such as myosin and kinesin.
Fundamentally, this work aims to develop and establish a high-speed, non-invasive camera on the nanoscale that will enable us to study and eventually understand nanoscopic motion, dynamics and potentials on the relevant, rather than currently achievable, size and time scales.
Summary
I propose to develop and apply a novel approach to optical microscopy to enable the direct visualization and study of dynamics on the nanoscale in biological and condensed matter physics. Given the speed with which nanoscopic objects move at ambient condition, this requires simultaneously very fast (ms) and precise (nm) imaging. The challenge is to avoid excessive perturbation of the system and enable imaging in biologically compatible environments without compromising imaging performance by pushing interferometric scattering to its theoretical limits.
Using these advanced capabilities, I will study the dynamics and thereby the structure-function relationships in three fundamental systems that are currently not captured by even the most advanced biophysical approaches. These include: (1) the flexibility of DNA on short length scales, (2) diffusion in artificial and cellular membranes and (3) the three-dimensional power stroke of molecular motors such as myosin and kinesin.
Fundamentally, this work aims to develop and establish a high-speed, non-invasive camera on the nanoscale that will enable us to study and eventually understand nanoscopic motion, dynamics and potentials on the relevant, rather than currently achievable, size and time scales.
Max ERC Funding
1 498 352 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym NCB-TNT
Project New chemical biology for tailoring novel therapeutics
Researcher (PI) James Henderson Naismith
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Advanced Grant (AdG), LS1, ERC-2013-ADG
Summary Most of our drugs derive from natural products, many more natural products possess biological activity but our inability to synthesise novel analogues hampers our ability to use them either as tools or medicines. Cyclic peptides are common structural motifs in natural products and medicines (vancomycin, gramicidin). They are widely recognised to constitute a promising and still underexploited class of molecule for novel therapeutics; specifically an important role for cyclic peptides in the inhibition of protein-protein interactions has been demonstrated. We will harness the power of the recently identified macrocyclases from the ribosomally-derived cyanobactin superfamily to prepare diverse modified cyclic peptides. These enzymes exhibit the remarkable ability to macrocyclise unactivated peptide substrates. Different members of this family of macrocyclases process peptides into macrocycles containing from six up to twenty residues. We have characterised and re-engineered one member of the family (PatG) which makes eight residue macrocycles. We will determine the structural and biochemical features of the macrocyclases that are known to lead to six or to twenty residue macrocycles. We will use these insights to put these enzymes to work in novel chemical reactions. We will combine macrocyclases with other enzymes from the cyanobactin biosynthetic pathways (whose structures and mechanism we have largely determined) and work on solid phase peptide substrates. By bringing together the power of solid phase methods (split and pool) and the novel chemistry enabled by the enzymes, we will generate highly diverse macrocyclic scaffolds containing amino acids, enzymatically modified amino acids, non-natural amino acids and non-amino acid building blocks. Successful completion of the project will revolutionise the design of cyclic peptide-inspired libraries with diverse backbone scaffolds for applications in target identification, drug discovery and tool screening.
Summary
Most of our drugs derive from natural products, many more natural products possess biological activity but our inability to synthesise novel analogues hampers our ability to use them either as tools or medicines. Cyclic peptides are common structural motifs in natural products and medicines (vancomycin, gramicidin). They are widely recognised to constitute a promising and still underexploited class of molecule for novel therapeutics; specifically an important role for cyclic peptides in the inhibition of protein-protein interactions has been demonstrated. We will harness the power of the recently identified macrocyclases from the ribosomally-derived cyanobactin superfamily to prepare diverse modified cyclic peptides. These enzymes exhibit the remarkable ability to macrocyclise unactivated peptide substrates. Different members of this family of macrocyclases process peptides into macrocycles containing from six up to twenty residues. We have characterised and re-engineered one member of the family (PatG) which makes eight residue macrocycles. We will determine the structural and biochemical features of the macrocyclases that are known to lead to six or to twenty residue macrocycles. We will use these insights to put these enzymes to work in novel chemical reactions. We will combine macrocyclases with other enzymes from the cyanobactin biosynthetic pathways (whose structures and mechanism we have largely determined) and work on solid phase peptide substrates. By bringing together the power of solid phase methods (split and pool) and the novel chemistry enabled by the enzymes, we will generate highly diverse macrocyclic scaffolds containing amino acids, enzymatically modified amino acids, non-natural amino acids and non-amino acid building blocks. Successful completion of the project will revolutionise the design of cyclic peptide-inspired libraries with diverse backbone scaffolds for applications in target identification, drug discovery and tool screening.
Max ERC Funding
2 499 991 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
