Projektbeschreibung
Die Zeit in der Chemie verstehen
Chemische Prozesse und die Chemie spielen eine entscheidende Rolle für zahlreiche Industrien, Innovationen und die Entwicklung neuer Werkzeuge und Technologien. Diese Fortschritte sind für die Bewältigung der mit dem Klimawandel verbundenen Herausforderungen ausschlaggebend. Leider wird die Bedeutung der Zeit in der Chemie oft übersehen, was zu Ineffizienzen bei Simulationen und in der Forschung führt. Daher wird im Projekt PASTIME, finanziert über den Europäischen Forschungsrat, ein methodischer Rahmen für die wirksame Einbeziehung und das Verständnis der Rolle der Zeit in der Chemie geschaffen. Das Ziel ist eine speicherabhängige Entnahmetechnik für Übergangsschnittstellenpfade für die chemische Modellierung. Diese Innovation könnte einen Durchbruch in der chemischen Simulation darstellen.
Ziel
Time matters: timescales determine the fate, behavior and functionality of living matter. Especially the interplay between fast and slow molecular processes is omnipresent in biochemistry (protein folding, enzymatic conversions, molecular signaling, etc.). However, in chemistry, models are lacking to properly understand time and its effect on this difficult biological reality.
PASTIME will lay the methodological foundations for a correct understanding of time in chemistry by introducing memory dependent transition interface path sampling to chemical modeling. We will tune the memory that is kept in simulations by creating new path ensemble definitions. The problem will be made computationally solvable by cutting molecules' pathways short. Long timescale effects will be studied through pathway statistics. We will achieve higher decorrelation in the sampling by designing new Monte Carlo moves in path space, such as alchemical moves that change the identity of atoms on the fly, and smart use of memory expansion with a replica exchange move. These new time concepts will be challenged and experimentally validated in a context of drug transport kinetics: drug (un)binding to protein binding sites, and permeation of molecules through cell membranes. The modeling principles will be converted to new algorithms that are computationally feasible today and will be shared in open software.
With PASTIME we will be able to understand slow time effects in molecular interactions. Appropriate memory reduction and tuning will give us the methods to understand time in an endless range of molecular processes, and this work will contribute to drug design, biochemistry, physiology, catalysis, material and polymer science.
Wissenschaftliches Gebiet
Schlüsselbegriffe
- molecular modeling
- statistical physics
- molecular dynamics simulations
- sampling of phase space
- Monte Carlo sampling
- binding kinetics
- binding and unbinding kinetics of protein-ligand
- binding sites
- drug transport
- drug delivery
- retention time
- timescales
- mutations
- screening
- liposomes
- phospholipids
- membrane permeability
- permeation
- lipid flipflop
- membrane asymmetry
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-ERC - HORIZON ERC GrantsGastgebende Einrichtung
9000 Gent
Belgien