Enhanced Sampling

Molecular dynamics is an important research method in the study of biomolecules, but is often limited by insufficient sampling. Enhanced sampling methods emerged to faster explore the conformational space of a biomolecular system. At Molecular Biophysics Stockholm, we develop and apply various enhanced sampling methods for different purposes. We show a few prominent examples below.

The String Method with Swarms of Trajectories

The string method with swarms of trajectories finds the most probable transition path between two end states. We developed a generalized protocol of the simulation method with automatic parameter selection, significantly reducing the efforts required to carry out and optimize this kind of simulation study. As a result, we could efficiently derive the activation pathway of a GPCR and the free energy landscape of activation. We use this method to study membrane proteins with well-defined end states to reveal the physiological transition mechanism. This method has been implemented as python package interfacing with gromacs and gmx-api and can be used freely.

Adaptive Sampling Methods
With adaptive sampling, we increase the efficiency of MD without applying an artificial force to the system. By running several simulation replicas in parallel and adaptively reseeding a subset of the replicas, we can enhance exploration of a proteins’ conformational landscape or derive single well-equilibrated states from a starting structure. We actively apply adaptive sampling to obtain a quantitative comparison of ligand induced GPCR states, as well as to refine Markov state models of Calmodulin.

Sergio Pérez-Conesa
Oliver Fleewood
Lucie Delemotte

Recent publications:

Identification of ligand-specific G protein-coupled receptor states and prediction of downstream efficacy via data-driven modeling Fleetwood, O., Carlsson, J., & Delemotte, L. (2021). Elife10, e60715

Energy landscapes reveal agonist’s control of GPCR activation via microswitches  Fleetwood, O., Matricon, P., Carlsson, J., & Delemotte, L. (2020). Energy landscapes reveal agonist control of G protein-coupled receptor activation via microswitches. Biochemistry59(7), 880-891.

Conformational landscapes of membrane proteins delineated by enhanced sampling molecular dynamics simulations TJ Harpole, L Delemotte, BBA Biomem, 1860 (4) 909-926

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