My research is aimed at an understanding of the biologically relevant processes involving all sorts of biomolecules from knowledge of their pairwise interactions, using the molecular dynamics simulation technique.
I am currently employed as head of the MD group at the University of Groningen, the Netherlands.
SJ Marrink, Dept of Biophysical Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands. Tel: 31-503634457. Email: s.j.marrink@rug.nl
Coarse Grained Model
Using coarse grained interaction sites instead of an atomistic representation of a lipid, four to five orders of speed up can be obtained. We developed a CG model that is not only fast, but also accurate in its predictions. Lipid area per headgroup, atom density distributions, bilayer bending modulus and line tension can all be reproduced to almost the same accuracy as with atomistic forcefields. The CG forcefield parameters and example input files plus a manual can be found here. CG model We are now working on an extension of our CG philosophy to include ring like molecules such as cholesterol, and to include a parameter set for peptide simulations.
Hexagonal Phase Formation
The transformation from a multilamellar to inverted hexagonal phase can be studied using the coarse grained lipid model. The phase diagram of mixtures of DOPC and DOPE can be reproduced to a large extent. Starting from the lamellar phase, the formation of the inverted hexagonal phase can be induced by heat, dehydration, or increasing the concentration of DOPE. Stalks are formed which elongate in a cooperative manner, separating the water phase into hexagonally ordered channels, characteristic of the inverted hexagonal phase. S.J. Marrink, A.E. Mark. Molecular view of hexagonal phase formation in phospholipid membranes. Biophys. J., 87:3894-3900, 2004.
Domain Formation
Formation of a gel phase in coarse grained lipid bilayers is shown to proceed via a nucleation and growth mechanism. For single component lipid bilayers the gel domains grow until the whole bilayer is converted to a gel phase: S.J. Marrink, J. Risselada, A.E. Mark. Simulation of gel phase formation and melting in lipid bilayers using a coarse grained model. Chem. Phys. Lip., 135:223-244, 2005., whereas for two component bilayers the end stage of the transformation is a two-phase coexistence between a gel phase enriched in the lipid with high chain melting temperature and a fluid phase enriched in the other component. R. Faller, S.J. Marrink. Simulation of domain formation in DLPC-DSPC mixed bilayers. Langmuir, 20:7686-7693, 2004.
Ripple Phase
The ripple phase is formed spontaneously in atomistic simulations of DPPC bilayers at low temperature. For the first time the molecular structure of the ripple phase, long debated, is now revealed. Surprisingly, the minor domain is not liquid-like but forms an interdigitated gel. The observed structural details are in agreement with experimental findings. We also calculated WAXS spectra which should allow for experimental verification of the proposed structure. A.H. de Vries, S. Yefimov, A.E. Mark, S.J. Marrink. Molecular structure of the lecithin ripple phase. Proc. Nat. Acad. Sci., 102:5392-5396, 2005.
Vesicle Formation and Fusion
Small unilamellar vesicles are spontaneously formed in solution. Using coarse grained models this proces can be simulated. The lipids first aggregate into interconnected worms. Subsequently a bicelle is formed, which encapsulates water to form a spherical vesicle. The whole proces takes ~200 ns. Currently vesicles up to a few thousend lipids can be simulated (diameter ~25 nm). S.J. Marrink, A.E. Mark. Molecular dynamics simulation of the formation, structure, and dynamics of small phospholipid vesicles. JACS, 125:15233-15242, 2003. When placed close to each other, these vesicle spontaneously fuse. The fusion mechanism is essentially that predicted by the stalk-model. S.J. Marrink, A.E. Mark. The mechanism of vesicle fusion as revealed by molecular dynamics simulations. of small phospholipid vesicles. JACS, 125:11144-11145, 2003. Formation of smaller vesicles can even be studied at atomic detail nowadays: A.H. de Vries, A.E. Mark, S.J. Marrink. Molecular dynamics simulation of the spontaneous formation of a small DPPC vesicle in atomistic detail. JACS, 126:4488-4489, 2004.
Membrane Pore
The structure and formation of water pores inside a lipid membrane is currently studied using atomistic simulations. When mechanical or electrical tension is applied, pores form and, at a critical tension threshold, completely disrupt the bilayer. This is in accordance with experimental findings. D.P. Tieleman, H. Leontiadou, A.E. Mark, S.J. Marrink. Simulation of pore formation in lipid bilayers under mechanical and electrical stress. JACS, 125:6382-6383, 2003. Below a critical tension, the pores can be stabilized and their equilibrium properties studied H. Leontiadou, A.E. Mark, S.J. Marrink. Molecular dynamics simulations of hydrophilic pores in lipid bilayers. Biophys. J., 86:2156-2164, 2004. Most recently we observed spontaneous pore formation by a specific member of the magainin family of antimicrobial peptides. As can be seen from the simulation snapshot, the structure of the formed pore deviates considerably from the idealized standard model of a toroidal pore H. Leontiadou, A.E. Mark, S.J. Marrink. Antimicrobial peptides in action. In press, 2006. . Pores are also observed in lipid monolayers under low surface pressure V. Knecht, M. Mueller, M. Bonn, S.J. Marrink, A.E. Mark. Molecular dynamics simulations of pore and domain formation in a phospholipid monolayer. J. Chem. Phys., 122, 024704, 2005.
Micelle Aggregation
Most atomistic simulations of micelles and bilayers thusfar start from a configuration in which the molecules are already in their target phase. We show that it is currently possible to observe the self-assembly of micelles and bilayers, starting from completely random solutions, at atomistic resolution. S.J. Marrink, D.P. Tieleman, and A.E. Mark. Molecular dynamics simulations of the kinetics of spontaneous micel formation. J. Phys. Chem. B, 104:12165-12173, 2000.
Bilayer Self-Assembly
Starting from random solutions of lipids we observe the self-assembly of lipid bilayers on nanosecond timescales in a number of steps. The first step is a rapid phase separation, followed by the formation of a primordial bilayer containing a hydrophilic water pore. The reduction of this pore is the rate limiting step towards the final formation of a normal bilayer. S.J. Marrink, E. Lindahl, O. Edholm, and A. Mark. Simulation of the spontaneous aggregation of phospholipids into bilayers. J. Am. Chem. Soc., 123:8638-8639, 2001.
Cubic Phases
One of the most intiguing bilayer phases is the so called cubic phase in which the lipids or surfactants form highly curved bilayers forming cubic lattices. For the first time we were able to simulate such a complicated phase using an atomic force field. S.J. Marrink and D.P. Tieleman. Molecular dynamics simulation of a lipid diamond cubic phase. J. Am. Chem. Soc., 123(49):12383-12391, 2001. We also simulated a complete phase transition from a cubic to a hexagonal phase! S.J. Marrink and D.P. Tieleman. Molecular dynamics simulation of spontaneous membrane fusion during a cubic - hexagonal phase transition. Biophys. J, 83:2386-2392, 2002.
Modelling Human Bile
Human bile mainly consists of a mixture of phospholipids, bilesalts and cholesterol. Under supersaturated conditions these components form mixed micelles. Using MD simulations we try to elucidate the structure of such micelles. S.J. Marrink and A.E. Mark. Molecular dynamics simulations of mixed micelles modelling human bile. Biochemistry, 41:5375-82, 2002.
Bilayer Pressure Profiles
Due to the inhomogeneous nature of the lipid bilayer, a stress profile exists, which may have important biological implications, i.e. in the regulation of the gating of mechanosensitive protein channels. G. Colombo, S.J. Marrink, A.E. Mark. Simulation of MscL gating in a bilayer under stress. Biophys. J, 84:2331-2337, 2003. MD simulations of bilayers allow the explicit computation of these stress profiles. A number of different lipids and lipid mixtures are currently studied.
Bilayer Undulations
Simulations of bilayers are necessarily performed on finite scale systems. As a consequence, long wavelength undulations are surpressed. The effect of surpression of undulations on surface tension and surface area is investigated in an extensive series of MD simulations of varying system sizes. S.J. Marrink and A.E. Mark. Effect of undulations on surface tension in simulated bilayers. J. Phys. Chem. B, 105:6122-6127, 2001.