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Doing Charges Right: Modelling Ion-Controlled Biological Processes with the Correct Toolbox

Project description

A charge-scaled force field model of ion-related biological processes

Biological systems rely on the flow of electrical charge for myriad signalling functions, often carried out by ions rather than electrons. Modelling these processes is a prerequisite to understanding them and harnessing the insight in therapies for ion-related pathologies. However, current models lack a description of an important effect of ions on the environment, namely electronic polarisation, which results in inaccuracies. Funded by the European Research Council, the Q-SCALING project will address this deficiency using machine learning techniques. The aim is to build a de novo comprehensive force field for biological systems that accounts for electronic polarisation in a mean-field way via charge scaling. The newly developed charge-scaled force field model will enable accurately addressing ion-specific processes from molecular to organ levels.

Objective

Electrical stimuli are essential for a plethora of biological functions. Unlike in electronics, where electrons form currents, nature rather exploits ions as charge carriers. Lack of a consistent molecular picture of action of ions impairs progress in fundamental understanding of ion-controlled biological processes and in designing smart strategies for fixing ion-related pathological conditions. Molecular simulations represent a powerful tool for modelling such processes, however, they can only be as good as is the underlying interaction model (force field). A major drawback of commonly used force fields is the lack of description of electronic polarization, which results in severe artifacts such as a dramatic over-binding of ions, preventing, e.g. accurate modelling of calcium signalling processes. This now well-recognized deficiency hampers faithful modelling of complex ion-involving biological processes.
We will employ machine learning techniques to build a de novo comprehensive force field for biological systems, that accounts for electronic polarization in a mean field way via charge scaling. This approach will qualitatively improve modelling of ions in biological contexts without additional computational costs. This will allow us to address accurately the following highly relevant ion-specific processes of increasing complexity from molecular over cellular to organ levels:
1. Dissolution of radical anions of aromatic molecules as key intermediates in technologically and biologically important non-enzymatic and enzymatic Birch reduction processes.
2. Direct membrane translocation of cationic cell penetrating peptides with a potential of drug delivery.
3. Circulation of calcium ions as signalling charge carriers through ion channels of hair cells in the cochlea.
At the same time, the newly developed charge scaled force field will be made freely available to the community for further development and ready to be used within major simulation program packages.

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Programme(s)

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Topic(s)

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Funding Scheme

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2022-ADG

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Host institution

USTAV ORGANICKE CHEMIE A BIOCHEMIE, AV CR, V.V.I.
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 2 499 115,00
Total cost

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€ 2 499 115,00

Beneficiaries (1)

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