Descripción del proyecto
Entender el tiempo en la química
Los procesos químicos y la química son importantísimos para muchas industrias e innovaciones, así como para el desarrollo de herramientas y tecnologías. Estos avances son esenciales para afrontar los retos del cambio climático. Por desgracia, a menudo se ha subestimado la importancia del tiempo en la química, lo que ha provocado ineficiencias en las simulaciones y la investigación. Teniendo esto en cuenta, en el proyecto PASTIME, financiado por el Consejo Europeo de Investigación, se pretende establecer un marco metodológico para incorporar y comprender de forma provechosa el papel del tiempo en la química. El objetivo del proyecto es crear una técnica de muestreo de trayectorias de interfaces de transición dependientes de la memoria para la modelización química. Esta innovación podría revolucionar el campo de las simulaciones químicas.
Objetivo
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.
Ámbito científico
Palabras clave
- 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
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC - HORIZON ERC GrantsInstitución de acogida
9000 Gent
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