Luca Monticelli

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.

Computer simulation study of fullerene translocation through lipid membranes.

Recent toxicology studies suggest that nanosized aggregates of fullerene molecules can enter cells and alter their functions, and also cross the blood-brain barrier. However, the mechanisms by which fullerenes penetrate and disrupt cell membranes are still poorly understood. Here we use computer simulations to explore the translocation of fullerene clusters through a model lipid membrane and the effect of high fullerene concentrations on membrane properties. The fullerene molecules rapidly aggregate in water but disaggregate after entering the membrane interior. The permeation of a solid-like fullerene aggregate into the lipid bilayer is thermodynamically favoured and occurs on the microsecond timescale. High concentrations of fullerene induce changes in the structural and elastic properties of the lipid bilayer, but these are not large enough to mechanically damage the membrane. Our results suggest that mechanical damage is an unlikely mechanism for membrane disruption and fullerene toxicity.

The molecular mechanism of lipid monolayer collapse

Lipid monolayers at an air–water interface can be compressed laterally and reach high surface density. Beyond a certain threshold, they become unstable and collapse. Lipid monolayer collapse plays an important role in the regulation of surface tension at the air–liquid interface in the lungs. Although the structures of lipid aggregates formed upon collapse can be characterized experimentally, the mechanism leading to these structures is not fully understood. We investigate the molecular mechanism of monolayer collapse using molecular dynamics simulations. Upon lateral compression, the collapse begins with buckling of the monolayer, followed by folding of the buckle into a bilayer in the water phase. Folding leads to an increase in the monolayer surface tension, which reaches the equilibrium spreading value. Immediately after their formation, the bilayer folds have a flat semielliptical shape, in agreement with theoretical predictions. The folds undergo further transformation and form either flat circular bilayers or vesicles. The transformation pathway depends on macroscopic parameters of the system: the bending modulus, the line tension at the monolayer–bilayer connection, and the line tension at the bilayer perimeter. These parameters are determined by the system composition and temperature. Coexistence of the monolayer with lipid aggregates is favorable at lower tensions of the monolayer–bilayer connection. Transformation into a vesicle reduces the energy of the fold perimeter and is facilitated for softer bilayers, e.g., those with a higher content of unsaturated lipids, or at higher temperatures.

Molecular Dynamics Simulation of a Palmitoyl-Oleoyl Phosphatidylserine Bilayer with Na+ Counterions and NaCl

Two 40 ns molecular dynamics simulations of a palmitoyl-oleoyl phosphatidylserine (POPS) lipid bilayer in the liquid crystalline phase with Na(+) counterions and NaCl were carried out to investigate the structure of the negatively charged lipid bilayer and the effect of salt (NaCl) on the lipid bilayer structure. Na(+) ions were found to penetrate deep into the ester region of the water/lipid interface of the bilayer. Interaction of the Na(+) ions with the lipid bilayer is accompanied by a loss of water molecules around the ion and a simultaneous increase in the number of ester carbonyl oxygen atoms binding the ion, which define an octahedral and square pyramidal geometry. The amine group of the lipid molecule is involved in the formation of inter- and intramolecular hydrogen bonds with the carboxylate and the phosphodiester groups of the lipid molecule. The area per lipid of the POPS bilayer is unaffected by the presence of 0.15M NaCl. There is a small increase in the order parameter of carbon atoms in the beginning of the alkyl chain in the presence of NaCl. This is due to a greater number of Na(+) ions being coordinated by the ester carbonyl oxygen atoms in the water/lipid interface region of the POPS bilayer.

On Atomistic and Coarse-Grained Models for C60 Fullerene

Many atomistic and coarse-grained simulations of fullerene and fullerene derivatives are reported in the literature, but validation of both atomistic and coarse-grained models has been very limited. Here, we report a thorough validation of several all-atom fullerene models and refinement of the MARTINI coarse-grained (CG) fullerene model. The all-atom model by Girifalco had been parametrized using only solid-state properties (lattice constant, heat of sublimation), but it performs well also in the liquid state in terms of partitioning between different solvents. The new MARTINI CG model is optimized by matching experimental free energies of transfer between different solvents (for fullerene-solvent interactions) and atomistic fullerene-fullerene potentials of mean force (PMF) in water and in octane (for fullerene-fullerene interactions). The model gives reasonable results for solid-state properties and also reproduces atomistic results on the PMF in a lipid membrane. We conclude that the new MARTINI model is suitable for large-scale simulations of the interaction of fullerene with water, organic solvents, and lipid membranes.

Computer simulation of the KvAP voltage-gated potassium channel: steered molecular dynamics of the voltage sensor

The recent crystal structures of the voltage‐gated potassium channel KvAP and its isolated voltage‐sensing ‘paddle’ (composed of segments S1–S4) challenge existing models of voltage gating and raise a number of questions about the structure of the physiologically relevant state. We investigate a possible gating mechanism based on the crystal structures in a 10 ns steered molecular dynamics simulation of KvAP in a membrane‐mimetic octane layer. The structure of the full KvAP protein has been modified by restraining the S2–S4 domain to the conformation of the isolated high‐resolution paddle structure. After an initial relaxation, the paddle tips are pulled through the membrane from the intracellular to the extracellular side, corresponding to a putative change from closed to open. We describe the effect of this large‐scale motion on the central pore domain, which remains largely unchanged, on the protein hydrogen‐bonding network and on solvent. We analyze the motion of the S3b–S4 portion of the protein and propose a possible coupling mechanism between the paddle motion and the opening of the channel. Interactions between the arginine residues in S4, solvent and chloride ions are likely to play a role in the gating charge.

Polystyrene Nanoparticles Perturb Lipid Membranes.

Polystyrene is abundant in marine debris. Like most synthetic polymers, it degrades very slowly, producing smaller and smaller particles easily ingested by wildlife. The presence of plastic microscopic particles in fish and marine wildlife is massive and well documented, but its impact on cellular activity is not understood. Biological activity generally requires interaction with biological membranes, but this is difficult to study at the molecular scale in vivo. Here we use coarse-grained molecular simulations to determine the effect of nanosized polystyrene (PS) particles on the properties of model biological membranes. We find that PS nanoparticles permeate easily into lipid membranes. Dissolved in the membrane core, PS chains alter membrane structure, significantly reduce molecular diffusion, and soften the membrane. Moreover, PS severely affects membrane lateral organization by stabilizing raft-like domains. Changes in membrane properties and lateral organization can severely affect the activity of membrane proteins and thereby cellular function.

Modeling the effect of nano-sized polymer particles on the properties of lipid membranes.

The interaction between polymers and biological membranes has recently gained significant interest in several research areas. On the biomedical side, dendrimers, linear polyelectrolytes, and neutral copolymers find application as drug and gene delivery agents, as biocidal agents, and as platforms for biological sensors. On the environmental side, plastic debris is often disposed of in the oceans and gets degraded into small particles; therefore concern is raising about the interaction of small plastic particles with living organisms. From both perspectives, it is crucial to understand the processes driving the interaction between polymers and cell membranes. In recent times progress in computer technology and simulation methods has allowed computational predictions on the molecular mechanism of interaction between polymeric materials and lipid membranes. Here we review the computational studies on the interaction between lipid membranes and different classes of polymers: dendrimers, linear charged polymers, polyethylene glycol (PEG) and its derivatives, polystyrene, and some generic models of polymer chains. We conclude by discussing some of the technical challenges in this area and future developments.

Toward Atomistic Resolution Structure of Phosphatidylcholine Headgroup and Glycerol Backbone at Different Ambient Conditions

Phospholipids are essential building blocks of biological membranes. Despite a vast amount of very accurate experimental data, the atomistic resolution structures sampled by the glycerol backbone and choline headgroup in phoshatidylcholine bilayers are not known. Atomistic resolution molecular dynamics simulations have the potential to resolve the structures, and to give an arrestingly intuitive interpretation of the experimental data, but only if the simulations reproduce the data within experimental accuracy. In the present work, we simulated phosphatidylcholine (PC) lipid bilayers with 13 different atomistic models, and compared simulations with NMR experiments in terms of the highly structurally sensitive C–H bond vector order parameters. Focusing on the glycerol backbone and choline headgroups, we showed that the order parameter comparison can be used to judge the atomistic resolution structural accuracy of the models. Accurate models, in turn, allow molecular dynamics simulations to be used as an interpretation tool that translates these NMR data into a dynamic three-dimensional representation of biomolecules in biologically relevant conditions. In addition to lipid bilayers in fully hydrated conditions, we reviewed previous experimental data for dehydrated bilayers and cholesterol-containing bilayers, and interpreted them with simulations. Although none of the existing models reached experimental accuracy, by critically comparing them we were able to distill relevant chemical information: (1) increase of choline order parameters indicates the P–N vector tilting more parallel to the membrane, and (2) cholesterol induces only minor changes to the PC (glycerol backbone) structure. This work has been done as a fully open collaboration, using nmrlipids.blogspot.fi as a communication platform; all the scientific contributions were made publicly on this blog. During the open research process, the repository holding our simulation trajectories and files (https://zenodo.org/collection/user-nmrlipids) has become the most extensive publicly available collection of molecular dynamics simulation trajectories of lipid bilayers.

Molecular simulation of multistate peptide dynamics: A comparison between microsecond timescale sampling and multiple shorter trajectories

Molecular dynamics simulations of the RN24 peptide, which includes a diverse set of structurally heterogeneous states, are carried out in explicit solvent. Two approaches are employed and compared directly under identical simulation conditions. Specifically, we examine sampling by two individual long trajectories (microsecond timescale) and many shorter (MS) uncoupled trajectories. Statistical analysis of the structural properties indicates a qualitative agreement between these approaches. Microsecond timescale sampling gives large uncertainties on most structural metrics, while the shorter timescale of MS simulations results in slight structural memory for beta‐structure starting states. Additionally, MS sampling detects numerous transitions on a relatively short timescale that are not observed in microsecond sampling, while long simulations allow for detection of a few transitions on significantly longer timescales. A correlation between the complex free energy landscape and the kinetics of the equilibrium is highlighted by principal component analysis on both simulation sets. This report highlights the increased precision of the MS approach when studying the kinetics of complex conformational change, while revealing the complementary insight and qualitative agreement offered by far fewer individual simulations on significantly longer timescales.