Mixing MARTINI: Electrostatic Coupling in Hybrid Atomistic–Coarse-Grained Biomolecular Simulations

Abstract

Hybrid molecular dynamics simulations of atomistic (AA) solutes embedded in coarse-grained (CG) environment can substantially reduce the computational cost with respect to fully atomistic simulations. However, interfacing both levels of resolution is a major challenge that includes a balanced description of the relevant interactions. This is especially the case for polar solvents such as water, which screen the electrostatic interactions and thus require explicit electrostatic coupling between AA and CG subsystems. Here, we present and critically test computationally efficient hybrid AA/CG models. We combined the Gromos atomistic force field with the MARTINI coarse-grained force field. To enact electrostatic coupling, two recently developed CG water models with explicit electrostatic interactions were used: the polarizable MARTINI water model and the BMW model. The hybrid model was found to be sensitive to the strength of the AA-CG electrostatic coupling, which was adjusted through the relative dielectric permittivity εr(AA-CG). Potentials of mean force (PMFs) between pairs of amino acid side chain analogues in water and partitioning free enthalpies of uncharged amino acid side chain analogues between apolar solvent and water show significant differences between the hybrid simulations and the fully AA or CG simulations, in particular for charged and polar molecules. For apolar molecules, the results obtained with the hybrid AA/CG models are in better agreement with the fully atomistic results. The structures of atomistic ubiquitin solvated in CG water and of a single atomistic transmembrane α-helix and the transmembrane portion of an atomistic mechanosensitive channel in CG lipid bilayers were largely maintained during 50-100 ns of AA/CG simulations, partly due to an overstabilization of intramolecular interactions. This work highlights some key challenges on the way toward hybrid AA/CG models that are both computationally efficient and sufficiently accurate for biomolecular simulations.

Adaptive resolution simulation of polarizable supramolecular coarse-grained water models

“…As a consequence, artifacts arise at the interfaces between water and other phases and in the vicinity of charged particles. 11,12 To address these issues, two CG water models with explicit charges have been recently introduced in combination a) s.j.marrink@rug.nl b) praprot@cmm.ki.si with the MARTINI force field, i.e., the polarizable water (PW) 13 and the big multipole water (BMW) 11 model. Both models use three sites per bead that, like the standard MAR-TINI, represent four water molecules.…”

“…The emerging multiscale simulation methods 12,[15][16][17][18][19][20] are the optimal way to tackle such situations as they bypass the trade-off between accuracy and efficiency of a model. The adaptive resolution scheme (AdResS) is such a method and allows one to simulate a system at multiple resolutions.…”

Computational ‘microscopy’ of cellular membranes

“…Hybrid models are, in principle, a very powerful simulation strategy because they combine the best of both worlds -sampling globally at a low resolution (for instance, the bulk membrane and solvent) with only a local high resolution in defined areas of interest (for instance, at the protein-lipid interface). Either a static division of the all-atom and coarse-grained degrees of freedom can be used (Han and Schulten, 2012;Rzepiela et al, 2011;Wassenaar et al, 2013), akin to the wellestablished hybrid quantum mechanics/molecular mechanics (QM/ MM) method, or an adaptive boundary that allows particles to change resolution during the simulation (Praprotnik et al, 2008;Zavadlav et al, 2014). A number of pioneering hybrid studies of the static kind have appeared, in which all-atom/based membrane proteins are embedded in a coarse-grained model membrane environment (Han and Schulten, 2012;Wassenaar et al, 2013).…”

“…Either a static division of the all-atom and coarse-grained degrees of freedom can be used (Han and Schulten, 2012;Rzepiela et al, 2011;Wassenaar et al, 2013), akin to the wellestablished hybrid quantum mechanics/molecular mechanics (QM/ MM) method, or an adaptive boundary that allows particles to change resolution during the simulation (Praprotnik et al, 2008;Zavadlav et al, 2014). A number of pioneering hybrid studies of the static kind have appeared, in which all-atom/based membrane proteins are embedded in a coarse-grained model membrane environment (Han and Schulten, 2012;Wassenaar et al, 2013). However, parameterization and implementation of all-atom/coarsegrained (AA/CG) hybrid models are quite challenging and have not yet been adapted to simulate large-scale cellular processes.…”

Adaptive resolution simulation of an atomistic protein in MARTINI water

“…Alternatively, multiscale schemes have been introduced usa) s.j.marrink@rug.nl b) praprot@cmm.ki.si ing particle-based models only, e.g., atomistic and physically simplified coarse-grained (CG) molecular models. 12 The coupling can be achieved either by a fixed resolution approach, where different resolution domains interact with each other but do not exchange molecules, [13][14][15][16][17][18][19][20] or the adaptive resolution approach, where molecules change their resolution according to their current positions. [21][22][23][24][25][26][27] Among the most advanced methods for the latter kind of simulations is the Adaptive Resolution Scheme (AdResS), 21,[28][29][30][31][32] which allows for concurrent coupling from quantum all the way to continuum length scales of molecular liquids and soft matter.…”