Djurre H. de Jong

Improved Parameters for the Martini Coarse-Grained Protein Force Field

The Martini coarse-grained force field has been successfully used for simulating a wide range of (bio)molecular systems. Recent progress in our ability to test the model against fully atomistic force fields, however, has revealed some shortcomings. Most notable, phenylalanine and proline were too hydrophobic, and dimers formed by polar residues in apolar solvents did not bind strongly enough. Here, we reparametrize these residues either through reassignment of particle types or by introducing embedded charges. The new parameters are tested with respect to partitioning across a lipid bilayer, membrane binding of Wimley-White peptides, and dimerization free energy in solvents of different polarity. In addition, we improve some of the bonded terms in the Martini protein force field that lead to a more realistic length of α-helices and to improved numerical stability for polyalanine and glycine repeats. The new parameter set is denoted Martini version 2.2.

The power of coarse graining in biomolecular simulations

Computational modeling of biological systems is challenging because of the multitude of spatial and temporal scales involved. Replacing atomistic detail with lower resolution, coarse grained (CG), beads has opened the way to simulate large‐scale biomolecular processes on time scales inaccessible to all‐atom models. We provide an overview of some of the more popular CG models used in biomolecular applications to date, focusing on models that retain chemical specificity. A few state‐of‐the‐art examples of protein folding, membrane protein gating and self‐assembly, DNA hybridization, and modeling of carbohydrate fibers are used to illustrate the power and diversity of current CG modeling.

Lipid packing drives the segregation of transmembrane helices into disordered lipid domains in model membranes

Cell membranes are comprised of multicomponent lipid and protein mixtures that exhibit a complex partitioning behavior. Regions of structural and compositional heterogeneity play a major role in the sorting and self-assembly of proteins, and their clustering into higher-order oligomers. Here, we use computer simulations and optical microscopy to study the sorting of transmembrane helices into the liquid-disordered domains of phase-separated model membranes, irrespective of peptide–lipid hydrophobic mismatch. Free energy calculations show that the enthalpic contribution due to the packing of the lipids drives the lateral sorting of the helices. Hydrophobic mismatch regulates the clustering into either small dynamic or large static aggregates. These results reveal important molecular driving forces for the lateral organization and self-assembly of transmembrane helices in heterogeneous model membranes, with implications for the formation of functional protein complexes in real cells.

Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function

A wide variety of phytochemicals are consumed for their perceived health benefits. Many of these phytochemicals have been found to alter numerous cell functions, but the mechanisms underlying their biological activity tend to be poorly understood. Phenolic phytochemicals are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examined five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochemicals alters lipid bilayer properties and the function of diverse membrane proteins. Molecular dynamics simulations show that these phytochemicals modify bilayer properties by localizing to the bilayer/solution interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochemicals, consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochemicals are due to cell membrane perturbations, rather than specific protein binding.

Martini straight: Boosting performance using a shorter cutoff and GPUs

Abstract In molecular dynamics simulations, sufficient sampling is of key importance and a continuous challenge in the field. The coarse grain Martini force field has been widely used to enhance sampling. In its original implementation, this force field applied a shifted Lennard-Jones potential for the non-bonded van der Waals interactions, to avoid problems related to a relatively short cutoff. Here we investigate the use of a straight cutoff Lennard-Jones potential with potential modifiers. Together with a Verlet neighbor search algorithm, the modified potential allows the use of GPUs to accelerate the computations in Gromacs. We find that this alternative potential has little influence on most of the properties studied, including partitioning free energies, bulk liquid properties and bilayer properties. At the same time, energy conservation is kept within reasonable bounds. We conclude that the newly proposed straight cutoff approach is a viable alternative to the standard shifted potentials used in Martini, offering significant speedup even in the absence of GPUs.

Characterization of thylakoid lipid membranes from cyanobacteria and higher plants by molecular dynamics simulations

The thylakoid membrane is mainly composed of non-common lipids, so called galactolipids. Despite the importance of these lipids for the function of the photosynthetic reaction centers, the molecular organization of these membranes is largely unexplored. Here we use multiscale molecular dynamics simulations to characterize the thylakoid membrane of both cyanobacteria and higher plants. We consider mixtures of up to five different galactolipids plus phosphatidylglycerol to represent these complex membranes. We find that the different lipids generally mix well, although nanoscale heterogeneities are observed especially in case of the plant membrane. The fluidity of the cyanobacterial membrane is markedly reduced compared to the plant membrane, even considering elevated temperatures at which thermophilic cyanobacteria are found. We also find that the plant membrane more readily undergoes a phase transformation to an inverted hexagonal phase. We furthermore characterized the conformation and dynamics of the cofactors plastoquinone and plastoquinol, revealing of the fast flip-flop rates for the non-reduced form. Together, our results provide a molecular view on the dynamical organization of the thylakoid membrane.

Dimerization of Amino Acid Side Chains : Lessons from the Comparison of Different Force Fields

The interactions between amino acid side chains govern protein secondary, tertiary, and quaternary structure formation. For molecular modeling approaches to be able to realistically describe these phenomena, the underlying force fields have to represent these interactions as accurately as possible. Here, we compare the side chain-side chain interactions for a number of commonly used force fields, namely the all-atom OPLS, the united-atom GROMOS, and the coarse-grain MARTINI force field. We do so by calculating the dimerization free energies between selected pairs of side chains and structural characterization of their binding modes. To mimic both polar and nonpolar environments, the simulations are performed in water, n-octanol, and decane. In general, reasonable correlations are found between all three force fields, with deviations on the order of 1 kT in aqueous solvent. In apolar solvent, however, significantly larger differences are found, especially for charged amino acid pairs between the OPLS and GROMOS force fields, and for polar interactions in the MARTINI force field in comparison to the higher resolution models. Interestingly, even in cases where the dimerization free energies are similar, the binding mode may differ substantially between the force fields. This was found to be especially the case for aromatic residues. In addition to the inter-force-field comparison, we compared the various force fields to a knowledge-based potential. The two independent approaches show good correlation in aqueous solvent with an exception of aromatic residues for which the interaction strength is lower in the knowledge-based potentials.

Gaussian curvature elasticity determined from global shape transformations and local stress distributions: a comparative study using the MARTINI model

We calculate the Gaussian curvature modulus kappa of a systematically coarse-grained (CG) one-component lipid membrane by applying the method recently proposed by Hu et al. [Biophys. J., 2012, 102, 1403] to the MARTINI representation of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). We find the value kappa/kappa = -1.04 +/- 0.03 for the elastic ratio between the Gaussian and the mean curvature modulus and deduce kappa(m)/kappa(m) = -0.98 +/- 0.09 for the monolayer elastic ratio, where the latter is based on plausible assumptions for the distance z0 of the monolayer neutral surface from the bilayer midplane and the spontaneous lipid curvature K(0m). By also analyzing the lateral stress profile sigma0(z) of our system, two other lipid types and pertinent data from the literature, we show that determining K(0m) and kappa through the first and second moment of sigma0(z) gives rise to physically implausible values for these observables. This discrepancy, which we previously observed for a much simpler CG model, suggests that the moment conditions derived from simple continuum assumptions miss the effect of physically important correlations in the lipid bilayer.

Determining equilibrium constants for dimerization reactions from molecular dynamics simulations

With todays available computer power, free energy calculations from equilibrium molecular dynamics simulations “via counting” become feasible for an increasing number of reactions. An example is the dimerization reaction of transmembrane alpha‐helices. If an extended simulation of the two helices covers sufficiently many dimerization and dissociation events, their binding free energy is readily derived from the fraction of time during which the two helices are observed in dimeric form. Exactly how the correct value for the free energy is to be calculated, however, is unclear, and indeed several different and contradictory approaches have been used. In particular, results obtained via Boltzmann statistics differ from those determined via the law of mass action. Here, we develop a theory that resolves this discrepancy. We show that for simulation systems containing two molecules, the dimerization free energy is given by a formula of the form ΔG ∝ ln(P1/P0). Our theory is also applicable to high concentrations that typically have to be used in molecular dynamics simulations to keep the simulation system small, where the textbook dilute approximations fail. It also covers simulations with an arbitrary number of monomers and dimers and provides rigorous error estimates. Comparison with test simulations of a simple Lennard Jones system with various particle numbers as well as with reference free energy values obtained from radial distribution functions show full agreement for both binding free energies and dimerization statistics.

Simulation of polyethylene glycol and calcium-mediated membrane fusion.

We report on the mechanism of membrane fusion mediated by polyethylene glycol (PEG) and Ca(2+) by means of a coarse-grained molecular dynamics simulation approach. Our data provide a detailed view on the role of cations and polymer in modulating the interaction between negatively charged apposed membranes. The PEG chains cause a reduction of the inter-lamellar distance and cause an increase in concentration of divalent cations. When thermally driven fluctuations bring the membranes at close contact, a switch from cis to trans Ca(2+)-lipid complexes stabilizes a focal contact acting as a nucleation site for further expansion of the adhesion region. Flipping of lipid tails induces subsequent stalk formation. Together, our results provide a molecular explanation for the synergistic effect of Ca(2+) and PEG on membrane fusion.