Senthil K. Kandasamy

The MARTINI Coarse-Grained Force Field: Extension to Proteins

Many biologically interesting phenomena occur on a time scale that is too long to be studied by atomistic simulations. These phenomena include the dynamics of large proteins and self-assembly of biological materials. Coarse-grained (CG) molecular modeling allows computer simulations to be run on length and time scales that are 2-3 orders of magnitude larger compared to atomistic simulations, providing a bridge between the atomistic and the mesoscopic scale. We developed a new CG model for proteins as an extension of the MARTINI force field. Here, we validate the model for its use in peptide-bilayer systems. In order to validate the model, we calculated the potential of mean force for each amino acid as a function of its distance from the center of a dioleoylphosphatidylcholine (DOPC) lipid bilayer. We then compared amino acid association constants, the partitioning of a series of model pentapeptides, the partitioning and orientation of WALP23 in DOPC lipid bilayers and a series of KALP peptides in dimyristoylphosphatidylcholine and dipalmitoylphosphatidylcholine (DPPC) bilayers. A comparison with results obtained from atomistic models shows good agreement in all of the tests performed. We also performed a systematic investigation of the partitioning of five series of polyalanine-leucine peptides (with different lengths and compositions) in DPPC bilayers. As expected, the fraction of peptides partitioned at the interface increased with decreasing peptide length and decreasing leucine content, demonstrating that the CG model is capable of discriminating partitioning behavior arising from subtle differences in the amino acid composition. Finally, we simulated the concentration-dependent formation of transmembrane pores by magainin, an antimicrobial peptide. In line with atomistic simulation studies, disordered toroidal pores are formed. In conclusion, the model is computationally efficient and effectively reproduces peptide-lipid interactions and the partitioning of amino acids and peptides in lipid bilayers.

Cation and anion transport through hydrophilic pores in lipid bilayers

To understand the origin of transmembrane potentials, formation of transient pores, and the movement of anions and cations across lipid membranes, we have performed systematic atomistic molecular dynamics simulations of palmitoyl-oleoyl-phosphatidylcholine (POPC) lipids. A double bilayer setup was employed and different transmembrane potentials were generated by varying the anion (Cl-) and cation (Na+) concentrations in the two water compartments. A transmembrane potential of approximately 350 mV was thereby generated per bilayer for a unit charge imbalance. For transmembrane potential differences of up to approximately 1.4 V, the bilayers were stable, over the time scale of the simulations (10-50 ns). At larger imposed potential differences, one of the two bilayers breaks down through formation of a water pore, leading to both anion and cation translocations through the pore. The anions typically have a short residence time inside the pore, while the cations show a wider range of residence times depending on whether they bind to a lipid molecule or not. Over the time scale of the simulations, we do not observe the discharge of the entire potential difference, nor do we observe pore closing, although we observe that the size of the pore decreases as more ions translocate. We also observed a rare lipid flip-flop, in which a lipid molecule translocated from one bilayer leaflet to the opposite leaflet, assisted by the water pore.