Project description
Smart data-driven techniques to model how biological molecules function
Biological motors, such as the V1Vo-ATPase, are molecular machines found in living cells that convert chemical energy into mechanical work with remarkable efficiency. However, understanding the atomic-level picture of their millisecond transitions between functional states is challenging owing to computational limitations. The ERC-funded MilliInMicro project proposes a holistic approach to bridge microsecond simulations with millisecond-scale biological processes. Researchers will use data-driven methods to determine key reaction coordinates with advanced algorithms for mapping free-energy pathways. They will also accelerate the process of exploring these pathways using advanced methods that map complex energy landscapes much faster than existing techniques. Project findings could illuminate the effects of disease-causing mutations and guide the design of artificial cells.
Objective
Complete understanding of how complex biological objects operate and fulfill their cellular role requires at its core a detailed picture of the millisecond (ms) conformational transitions between functional states. Computational investigation of such ms–events is thwarted by our difficulty—and often impossibility—to identify and sample efficiently the relevant degrees of freedom at play, as well as the current limitation of all-atom molecular dynamics to the microsecond (μs) timescale on common computer architectures. Guided by concrete biological questions that experiment alone has hitherto proven unable to address, we propose a holistic approach to bridge affordable μs–computer simulations and ms–biological processes without the aid of a special-purpose supercomputer. To meet this grand theoretical challenge, we will associate two powerful developments to make the quantum leap, and open a breadth of applications, scaling up to very large biological objects, so far inaccessible to μs–timescale computer simulations. First, we will determine the reaction coordinate in an unprecedented combination of data- driven discovery of collective variables and advanced algorithms to find the minimum free-energy pathway that connects the end states of the conformational transition. Second, we will accelerate sampling along this pathway by associating ergodic schemes to a novel approach that maps complex free-energy landscapes significantly faster than its competitors. We will apply this methodology to a V1Vo–ATPase, a complete ATP–driven biological motor that converts over the ms–timescale the chemical energy of ATP hydrolysis into mechanical work, with minimalist dissipation. Beyond illuminating the allosteric pathways that underlie the conformational transition, atomic-level description of the rotary-catalysis milestones will shed new light on the effects of pathological mutations altering ATP activity, while helping engineer artificial cells with accelerated ATP turnover.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics mutation
- engineering and technology electrical engineering, electronic engineering, information engineering electronic engineering computer hardware supercomputers
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2022-ADG
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75794 PARIS
France
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