General Purpose Coarse-Grained Force Field

Article27

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Last Updated: Wednesday, 21 August 2013 11:20

A. Milani, M. Casalegno, C. Castiglioni, G. Raos. Coarse-Grained Simulations of Model Polymer Nanofibres, Macromol. Th. Sim.  ASAP, 2011.

We describe the development of a coarse-grained (CG) force field for nylon-6 (polycaprolactam) and its application to the simulation of the structure and macromolecular dynamics within cylindrical fibres formed by this polymer, having diameters in the 14–28 nm range. Our CG model is based on the MARTINI force field for the non-bonded interactions and on Boltzmann- inverted gas-phase atomistic simulations for intramolecular stretching and bending energies. The simulations are carried out on infinite, isolated nanofibres at temperatures of 300, 400 and 500 K, with different starting configurations. Starting from ordered chain-extended configurations, we simulate the melting of the polymer in the nanofibres and, after cooling back to room temperature, its re-crystallization in a chain-folded lamellar configuration. This agrees with experimental observations on electrospun nylon-6 nanofibres and demon- strated the suitability of the approach for the simulation of these systems. The effect of nanoscale confinement on the structure and dynamics of the polymer chains is extensively discussed.

Article26

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Last Updated: Wednesday, 21 August 2013 11:20

H. Lee and R.W. Pastor. Coarse-Grained Model for PEGylated Lipids: Effect of PEGylation on the Size and Shape of Self-Assembled Structures. J. Phys. Chem. B, ASAP, 2011. doi:10.1021/jp2020148

Self-assembly of polyethylene glycol (PEG)-grafted lipids at different sizes and concentrations was simulated using the MARTINI coarse-grained (CG) force field. The interactions between CG PEG and CG dipalmitoylglycerophosphocholine (DPPC)-lipids were parametrized by matching densities of 19-mers of PEG and polyethylene oxide (PEO) grafted to the bilayer from all-atom simulations. Mixtures of lipids and PEG-grafted (Mw = 550, 1250, and 2000) lipids in water self-assembled to liposomes, bicelles, and micelles at different ratios of lipids and PEGylated lipids. Average aggregate sizes decrease with increasing PEGylated-lipid concentration, in qualitative agreement with experiment. PEGylated lipids concentrate at the rims of bicelles, rather than at the planar surfaces; this also agrees with experiment, though the degree of segregation is less than that assumed in previous modeling of the experimental data. Charged lipids without PEG evenly distribute at the rim and planar surfaces of the bicelle. The average end-to-end distances of the PEG on the PEGylated lipids are comparable in liposomes, bicelles (edge or planar surface), and micelles and only slightly larger than for an isolated PEG in solution. The ability of PEGylated lipids to induce the membrane curvature by the bulky headgroup with larger PEG, and thereby modulate the phase behavior and size of lipid assemblies, arises from their relative concentration.

Article25

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Last Updated: Wednesday, 21 August 2013 11:20

A.J. Rzepiela, M. Louhivuori, C. Peter, S.J. Marrink. Hybrid simulations: combining atomistic and coarse-grained force fields using virtual sites. Phys. Chem. Chem. Phys., ASAP, 2011, DOI:10.1039/C0CP02981E

Hybrid simulations, in which part of the system is represented at atomic resolution and the remaining part at a reduced, coarse-grained, level offer a powerful way to combine the accuracy associated with the atomistic force fields to the sampling speed obtained with coarse-grained (CG) potentials. In this work we introduce a straightforward scheme to perform hybrid simulations, making use of virtual sites to couple the two levels of resolution. With the help of these virtual sites interactions between molecules at different levels of resolution, i.e. between CG and atomistic molecules, are treated the same way as the pure CG–CG interactions. To test our method, we combine the Gromos atomistic force field with a number of coarse-grained potentials, obtained through several approaches that are designed to obtain CG potentials based on an existing atomistic model, namely iterative Boltzmann inversion, force matching, and a potential of mean force subtraction procedure (SB). We also explore the use of the MARTINI force field for the CG potential. A simple system, consisting of atomistic butane molecules dissolved in CG butane, is used to study the performance of our hybrid scheme. Based on the potentials of mean force for atomistic butane in CG solvent, and the properties of 1:1 mixtures of atomistic and CG butane which should exhibit ideal mixing behavior, we conclude that the MARTINI and SB potentials are particularly suited to be combined with the atomistic force field. The MARTINI potential is subsequently used to perform hybrid simulations of atomistic dialanine peptides in both CG butane and water. Compared to a fully atomistic description of the system, the hybrid description gives similar results provided that the dielectric screening of water is accounted for. Within the field of biomolecules, our method appears ideally suited to study e.g. protein-ligand binding, where the active site and ligand are modeled in atomistic detail and the rest of the protein, together with the solvent, is coarse-grained.

Protein-Ligand Binding

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Last Updated: Wednesday, 25 January 2023 14:23

Binding of ligands to proteins is a challenging area for coarse-grained models. Most binding pockets require specific hydrogen bonding patterns and a neat fit of the ligand. With a CG model such as Martini that lacks directional hydrogen bonds and can not represent the fine details of the packing, ligand binding may require multi-scale methods.

However, less specific binding may be modeled with Martini, and more and more examples are appearing in the literature, such as the binding of cofactors to photosynthetic membrane complexes [2],  and the binding of a peptide to the OppA transport receptor [1].

Importantly, the new version of Martini, Martini 3, has opened the way to study protein-ligand binding on a much larger scale. Due to the improved description of small bead types, and the better representation of molecular geometries as well as cavities in proteins, the binding of small ligands to a variety of protein targets can now be faithfully (and very effciently !) captured with Martini, as shown in a recent proof of concept [3, see Figure]. A prospective of using this approach to build a high-throughput drug screening pipeline is presented in [4]. More examples of Martini 3 applied to predict protein-ligand interactions are found in [5].

[1] R.P.A. Berntsson, M.K. Doeven, F. Fusetti, R.H. Duurkens, D. Sengupta, S.J. Marrink, A.M.W.H. Thunnissen, B. Poolman, D.J. Slotboom. The structural basis for peptide selection by the transport receptor OppA. EMBO J., 28:1332-1340, 2009. open access

[2] F.J. van Eerden, M.N. Melo, P.W.J.M. Frederix, X. Periole, S.J. Marrink. Exchange pathways of plastoquinone and plastoquinol in the photosystem II complex. Nature Commun. 8:15214, 2017. open access

[3] P.C.T. Souza, S. Thallmair, P. Conflitti, C. Ramírez-Palacios, R. Alessandri, S. Raniolo, V. Limongelli,  S.J. Marrink. Protein–ligand binding with the coarse-grained Martini model. Nature Commun. 11:3714, 2020. doi:10.1038/s41467-020-17437-5

[4] P.C.T. Souza, V. Limongelli, S. Wu, S.J. Marrink, L. Monticelli. Perspectives on High-Throughput Ligand/Protein Docking With Martini MD Simulations. Front. Mol. Biosciences 8:657222, 2021. doi:10.3389/fmolb.2021.657222

[5] B. Waclawiková, P.C.T. Souza, M. Schwalbe, C.G. Neochoritis, W. Hoornenborg, S.A. Nelemans, S.J. Marrink, S. El Aidy. Potential binding modes of the gut bacterial metabolite, 5-hydroxyindole, to the intestinal L-type calcium channels and its impact on the microbiota in rats. Gut Microbes 15 (1), 2154544, 2023. doi:10.1080/19490976.2022.2154544

Article24

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Last Updated: Wednesday, 21 August 2013 11:20

"Interleaflet Interaction and Asymmetry in Phase Separated Lipid Bilayers: Molecular Dynamics Simulations", Jason D. Perlmutter and Jonathan N. Sachs, J. Am. Chem. Soc., ASAP, 2011. DOI: 10.1021/ja106626r

In order to investigate experimentally inaccessible, molecular-level detail regarding interleaflet interaction in membranes, we have run an extensive series of coarse-grained molecular dynamics simulations of phase separated lipid bilayers. The simulations are motivated by differences in lipid and cholesterol composition in the inner and outer leaflets of biological membranes. Over the past several years, this phenomenon has inspired a series of experiments in model membrane systems which have explored the effects of lipid compositional asymmetry in the two leaflets. The simulations are directed at understanding one potential consequence of compositional asymmetry, that being regions of bilayers where liquid-ordered (Lo) domains in one leaflet are opposite liquid-disordered (Ld) domains in the other leaflet (phase asymmetry). The simulated bilayers are of two sorts: 1) Compositionally symmetric leaflets where each of the two leaflets contains an identical, phase separated (Lo/Ld) mixture of cholesterol, saturated and unsaturated phospholipid; and 2) Compositionally asymmetric leaflets, where one leaflet contains a phase separated (Lo/Ld) mixture while the other contains only unsaturated lipid, which on its own would be in the Ld phase. In addition, we have run simulations where the lengths of the saturated lipid chains as well as the mole ratios of the three lipid components are varied. Collectively, we report on three types of interleaflet coupling within a bilayer. First, we show the effects of compositional asymmetry on acyl chain tilt and order, lipid rotational dynamics, and lateral diffusion in regions of leaflets that are opposite Lo domains. Second, we show substantial effects of compositional asymmetry on local bilayer curvature, with the conclusion that phase separated leaflets resist curvature, while inducing large degrees of curvature in an opposing Ld leaflet. Finally, in compositionally symmetric, phase separated bilayers, we find phase asymmetry (domain antiregistration) between the two leaflets occurs as a consequence of mismatched acyl chain-lengths in the saturated and unsaturated lipids.

Article23

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Last Updated: Wednesday, 21 August 2013 11:20

"Curvature-Dependent Elastic Properties of Liquid-Ordered Domains Result in Inverted Domain Sorting on Uniaxially Compressed Vesicles", H.J. Risselada, S.J. Marrink, M. Muller, Phys. Rev. Lett., 106:148102, 2011

Using a coarse-grained molecular model we study the spatial distribution of lipid domains on a 20-nm-sized vesicle. The lipid mixture laterally phase separates into a raftlike, liquid-ordered (lo) phase and a liquid-disordered phase. As we uniaxially compress the mixed vesicle keeping the enclosed volume constant, we impart tension onto the membrane. The vesicle adopts a barrel shape, which is composed of two flat contact zones and a curved edge. The lo domain, which exhibits a higher bending rigidity, segregates to the highly curved edge. This inverted domain sorting switches to normal domain sorting, where the lo domain prefers the flat contact zone, when we release the contents of the vesicle. We rationalize this domain sorting by a pronounced reduction of the bending rigidity and area compressibility of the lo phase upon bending.