A Novel, Systematic Multiscale Modeling Method to Calculate Coarse-Grained Parameters for the Simulation of Biomolecules

We developed new intermediate resolution implicit solvent models for lipids, "LIME" and DNA molecules, "DIME," designed for use with discontinuous molecular dynamics (DMD) simulations. A multi-scale modeling approach was used to extract both the LIME and DIME parameters from explicit solvent atomistic simulations. We applied LIME to study the spontaneous formation of lipid bilayers, the behavior of mixed lipid systems at different pH values and the interaction between membranes and nanoparticles. DIME was used to investigate the structural properties of DNA and the process by which two DNA strands hybridize in solution.;In LIME, 14 coarse-grained sites that are classified as 1 of 6 types represent DPPC. DMD simulations performed on a random solution of DPPC lipids resulted in the spontaneous formation of a defect free bilayer in less than 4 hours. The speed at which the formation of the bilayer was observed is close to an order of magnitude faster than the fastest reported speed for a coarse-grained, implicit solvent model. The bilayer formed quantitatively reproduces the main structural properties (e.g. area per lipid, bilayer thickness, bond order parameters) that are observed experimentally. In addition, the bilayer transitions from a liquid-crystalline phase to a tilted gel phase when the temperature is reduced. Transbilayer movement of a lipid from the bottom leaflet to the top leaflet is observed when the temperature is increased.;Our initial LIME model was extended to include the description of the geometry and energetics of DPPC, 1,2-distearoyl-sn-glycero-3-phospho-L-serine (DSPS) and 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine (21PC) at both neutral and low pH at 310K. In the model, 14 coarse-grained sites represent DPPC, 17 coarse-grained sites represent DSPS and 18 coarse-grained sites represent 21PC. Each of these coarse-grained sites is classified as 1 of 10 types. LIME/DMD simulations performed on bilayers containing different compositions of DPPC/DSPS and 21PC/DSPS showed similar heterogeneous domain formation at both a neutral and low pH.;We demonstrate how the combination of DMD and LIME can be used to model the interaction between lipid membranes and nanoparticles of different sizes, densities and hydrophobicities. In this work we run "proof of concept" simulations to demonstrate that our model can be evolved to examine more specific nanoparticle-membrane systems. We studied the wrapping process for nanoparticles with diameters from 5A to 100A and found that DPPC bilayers do not wrap nanoparticles with a diameter less than 20A. Instead, we found that these particles become embedded in the bilayer surface where they can easily interact with the hydrophilic head groups of the lipid molecules. We also investigated the interaction between hydrophobic nanoparticles with diameters from 5A to 40A. According to our results, the hydrophobic nanoparticles do not undergo the wrapping process; instead they directly penetrate the membrane and embed themselves within the inner hydrophobic core of the bilayers. The density of the hydrophilic and hydrophobic nanoparticles did not appear to affect the way in which they interact with the membranes.;In DIME, three coarse-grained sites are used to represent each nucleotide (one for each sugar, phosphate and base molecule). Each of these coarse-grained sites is classified as 1 of 6 types for sugar, phosphate, cytosine, guanine, adenine and thymine. DMD simulations performed on an initial random configuration of two single-stranded Dickerson-Drew dodecamer chains resulted in the formation of a double-helical structure within approximately 0.17 CPU hours. An alternative procedure for calculating the square-well width for each pair of interaction sites, which involves the second virial coefficient, was also investigated. Simulations run using this second set of parameters did not result in the spontaneous formation of a double helix even though the double helix remained stable at low temperature.