The Molecular Simulation Group

Development of Hybrid AA/CG Methods for Biomolecular Simulations


Hybrid AA/CG models in which atomistic solutes (e.g., proteins) are embedded in a coarse-grained environment (e.g., water and lipids) can substantially increase the computational efficiency as compared to fully atomistic simulations. However, interfacing both levels of resolution is a major challenge that requires a balanced description of all relevant interactions, i.e., AA-AA, CG-CG, and AA-CG. We develop and critically test hybrid AA/CG schemes that combine different atomistic and coarse-grained force fields in such a way that electrostatic interactions between the two regimes are explicitly taken into account. This coupling is particularly important for polar solvents, such as water, that screen the electrostatic interactions.

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Atomistic solutes surrounded by CG solvent. We systematically evaluate such hybrid AA/CG models by means of free energy calculations: How fast and how accurate are they?

To enact electrostatic coupling, we use various recently developed polarizable CG water models. Potentials of mean force (PMFs) between pairs of amino acid side chains and solvation free energies of amino acid side chains obtained from the hybrid AA/CG simulations are compared to the respective data from fully AA and fully CG simulations, and from experiments if available. Finally, the structure and dynamics of small atomistic proteins in CG water and of atomistic membrane proteins embedded in solvated CG lipid bilayers are studied, with a focus on the observed over-stabilisation of intra-protein interactions due to the lacking hydrogen bonding capability of the CG solvent. Our work highlights some of the key challenges — and suggests possible solutions — on the way toward hybrid AA/CG models that are both computationally efficient and at the same time sufficiently accurate to address biomolecular systems.