Grained Force Field Research Articles

Exploring the Properties of Curved Lipid Membranes: Comparative Analysis of Atomistic and Coarse-Grained Force Fields.

Curvature emerges as a fundamental membrane characteristic crucial for diverse biological processes, including vesicle formation, cell signaling, and membrane trafficking. Increasingly valuable insights into atomistic details governing curvature-dependent membrane properties are provided by computer simulations. Nevertheless, the underlying force field models are conventionally calibrated and tested in relation to experimentally derived parameters of planar bilayers, thereby leaving uncertainties concerning their consistency in reproducing curved lipid systems. In this study we compare the depiction of buckled phosphatidylcholine (POPC) and POPC-cholesterol membranes by four popular force field models. Aside from agreement with respect to general trends in curvature dependence of a number of parameters, we observe a few qualitative differences. Among the most prominent ones is the difference between atomistic and coarse grained force fields in their representation of relative compressibility of the polar headgroup region and hydrophobic lipid core. Through a number of downstream effects, this discrepancy can influence the way in which curvature modulates the behavior of membrane bound proteins depending on the adopted simulation model.

Homogeneous nucleation of crystalline methane hydrate in molecular dynamics transition paths sampled under realistic conditions.

Methane hydrates are important from a scientific and industrial perspective, and form by nucleation and growth from a supersaturated aqueous solution of methane. Molecular simulation is able to shed light on the process of homogeneous nucleation of hydrates, using straightforward molecular dynamics or rare event enhanced sampling techniques with atomistic and coarse grained force fields. In our previous work [Arjun, T. A. Berendsen, and P. G. Bolhuis, Proc. Natl. Acad. Sci. U. S. A. 116, 19305 (2019)], we performed transition path sampling (TPS) simulations using all atom force fields under moderate driving forces at high pressure, which enabled unbiased atomistic insight into the formation of methane hydrates. The supersaturation in these simulations was influenced by the Laplace pressure induced by the spherical gas reservoir. Here, we investigate the effect of removing this influence. Focusing on the supercooled, supersaturated regime to keep the system size tractable, our TPS simulations indicate that nuclei form amorphous structures below roughly 260K and crystalline sI structures above 260K. For these temperatures, the average transition path lengths are significantly longer than in our previous study, pushing the boundaries of what can be achieved with TPS. The temperature to observe a critical nucleus of certain size was roughly 20K lower compared to a spherical reservoir due to the lower concentration of methane in the solution, yielding a reduced driving force. We analyze the TPS results using a model based on classical nucleation theory. The corresponding free energy barriers are estimated and found to be consistent with previous predictions, thus adding to the overall picture of the hydrate formation process.

Transferable and Polarizable Coarse Grained Model for Proteins─ProMPT.

The application of classical molecular dynamics (MD) simulations at atomic resolution (fine-grained level, FG), to most biomolecular processes, remains limited because of the associated computational complexity of representing all the atoms. This problem is magnified in the presence of protein-based biomolecular systems that have a very large conformational space, and MD simulations with fine-grained resolution have slow dynamics to explore this space. Current transferable coarse grained (CG) force fields in literature are either limited to only peptides with the environment encoded in an implicit form or cannot capture transitions into secondary/tertiary peptide structures from a primary sequence of amino acids. In this work, we present a transferable CG force field with an explicit representation of the environment for accurate simulations with proteins. The force field consists of a set of pseudoatoms representing different chemical groups that can be joined/associated together to create different biomolecular systems. This preserves the transferability of the force field to multiple environments and simulation conditions. We have added electronic polarization that can respond to environmental heterogeneity/fluctuations and couple it to protein's structural transitions. The nonbonded interactions are parametrized with physics-based features such as solvation and partitioning free energies determined by thermodynamic calculations and matched with experiments and/or atomistic simulations. The bonded potentials are inferred from corresponding distributions in nonredundant protein structure databases. We present validations of the CG model with simulations of well-studied aqueous protein systems with specific protein fold types─Trp-cage, Trpzip4, villin, WW-domain, and β-α-β. We also explore the applications of the force field to study aqueous aggregation of Aβ 16-22 peptides.

SPICA Force Field for Proteins and Peptides.

A coarse-grained (CG) model for peptides and proteins was developed as an extension of the Surface Property fItting Coarse grAined (SPICA) force field (FF). The model was designed to examine membrane proteins that are fully compatible with the lipid membranes of the SPICA FF. A preliminary version of this protein model was created using thermodynamic properties, including the surface tension and density in the SPICA (formerly called SDK) FF. In this study, we improved the CG protein model to facilitate molecular dynamics (MD) simulations with a reproduction of multiple properties from both experiments and all-atom (AA) simulations. An elastic network model was adopted to maintain the secondary structure within a single chain. The side-chain analogues reproduced the transfer free energy profiles across the lipid membrane and demonstrated reasonable association free energy (potential of mean force) in water compared to those from AA MD. A series of peptides/proteins adsorbed onto or penetrated into the membrane simulated by the CG MD correctly predicted the penetration depths and tilt angles of peripheral and transmembrane peptides/proteins as comparable to those in the orientations of proteins in membranes (OPM) database. In addition, the dimerization free energies of several transmembrane helices within a lipid bilayer were comparable to those from experimental estimation. Application studies on a series of membrane protein assemblies, scramblases, and poliovirus capsids demonstrated the good performance of the SPICA FF.

Recent Open Issues in Coarse Grained Force Fields.

This viewpoint intends to show recent open issues of using coarse grained models in molecular dynamics simulation. It reviews the current knowledge of the comparison between experimental and simulation data of structural and physical chemical properties that depend on the hydrophilic and hydrophobic behavior of the molecule.

Determining the Bending Moduli of Asymmetric Bilayers by Simulation

Biological membranes are almost always asymmetric in terms of lipid composition. Such asymmetry is thought to play an important part in biological functions via alteration of the membrane's elastic properties, including its bending modulus. Recently experimental techniques have been developed which enable the preparation of asymmetric GUVs and therefore allow the measurement and direct comparison of bending moduli for pure bilayers, mixed symmetric bilayers and asymmetric bilayers composed of similar lipid species. These experiments show that asymmetry does indeed have a marked effect on bilayer stiffness. In order to reproduce these data and develop a molecular level understanding of them, we have taken a computational approach using both atomistic and coarse grained forcefields for a variety of system sizes and lipid species. We have performed analysis of our trajectories using a range of theoretical models based on a variety of different analysis techniques including those based directly on membrane area compressibility; those based on spectral analysis involving 2D discrete Fourier transforms; and those based on the distribution of angles of splay. Our results show that the different models employed provide consistent results across a range of system sizes both with each other and the experimental data, as well as suggesting promising new directions for experimental investigation.

All-atom and coarse-grained force fields for polydimethylsiloxane

By combining the bottom-up and top-down approaches, we have developed a new all-atom (AA) force field from quantum mechanics and experimental data and a new coarse grained (CG) force field from AA simulation and experimental data, for polydimethylsiloxane (PDMS). The AA force field is developed based on the TEAM force field database. The CG force field uses a mapping rule that splits the connecting oxygen into neighbouring CG beads to maintain the charge neutrality of the beads, analytical functional forms including anharmonic terms in the valence terms, and the temperature-dependent free-energy functional form to describe the inter-bead interactions. Broad range of thermodynamic properties of PDMS including density, surface tension, solubility parameter, radius of gyration and glass transition temperature are calculated to validate the force fields, and good agreements with the experimental data are obtained.

Investigation of a Method to Efficiently Create Elastic Networks

Elastic Networks (EN) have proven useful in the study of proteins, where they have a wide range of applications, from modeling the normal mode fluctuations of a protein to amending coarse grained (CG) force fields in order to conserve secondary and tertiary structures. In this project, we investigate the effectiveness of a systematic method for coarse-graining a protein (or part of a protein) into an EN where a substantial fraction of the particles are removed. The method begins with the creation of a Gaussian Network Model (GN) from either a high resolution EN or an all atom protein reference conformation and force field. By virtue of the GN being quadratic, we can analytically integrate out any number of degrees of freedom to create a CG GN with the same free energy as the original GN. Unfortunately, we cannot exactly transform the CG GN back to an EN because the GN no longer represents only central force interactions between particles. However, we can approximate the GN using an EN where the accuracy of the EN depends on the choice of particles that are removed. We show that a judicious choice of the configuration can significantly improve the accuracy of the EN. We discuss the ability of different optimization processes to efficiently find an optimum choice of the remaining particles. Finally, we investigate how well the resulting EN can replicate observables from the original system.

A Structurally Flexible Protein Backbone for the MARTINI Coarse Grained Force Field

By reducing the level of description of a system as compared to atomistic models coarse grained (CG) molecular force fields allow simulating larger systems for longer time scales, thereby probing exciting properties of biological systems. It is our constant effort to improve their accuracy and range of applicability. The MARTINI CG model defines a library of beads or super-atoms corresponding to chemical entities (defined by 3-6 non-H atoms) for which the interaction strengths are parameterized against thermodynamic (partitioning free energies) and structural data extracted from experiments and simulations. Virtually any molecular topology can be built from a combination of beads that reproduces structural and thermodynamic available data for that particular molecule. Molecular topologies are available for a large variety of molecules including lipids, amino acids and proteins, and sugars. Here we present a refined version of the MARTINI force field for proteins in which restraining the secondary structure is not required anymore. This is achieved by restoring directionality in the backbone interactions. To do so a dipole (two net charges kept at a fix distance) is placed on the peptide bond of the backbone. We show that this simple representation coupled with a rigorous parameterization of the dipole and related bonded/non-bonded interactions is able to capture some essential mechanical and physicochemical properties of the polypeptide backbone. In particular the backbone may access both extended (β-sheet) and compact (α-helix) conformations using a single potential. A few simple test cases are shown to illustrate the structural flexibility of the new backbone and its ability to stabilize secondary structure elements in proteins. The potential is tested with both regular and polarizable MARTINI water models.

Parametrization and Application of a Coarse Grained Force Field for Benzene/Fullerene Interactions with Lipids

Recently, we reported new coarse grain (CG) force fields for lipids and phenyl/fullerene based molecules. Here, we developed the cross parameters necessary to unite those force fields and then applied the model to investigate the nature of benzene and C(60) interactions with lipid bilayers. The interaction parameters between the phenyl and lipid CG sites are based on experimental and all atom (AA) molecular dynamics (MD) data. The resulting force field was tested on benzene rich lipid bilayers and shown to reproduce general behavior expected from experiments. The parameters were then applied to C(60) interactions with lipid bilayers. Overall, the results showed excellent agreement with AA MD and experimental observations. In the C(60) lipid systems, the fullerenes were shown to aggregate even at the lowest concentrations investigated.

Parametrization and Validation of Coarse Grained Force-Fields Derived from ab Initio Calculations.

A novel multisite interaction potential, suitable for computer simulations of complex materials as liquid crystals or polymers, is proposed and parametrized. Its validation is achieved through Monte Carlo numerical experiments at constant temperature and pressure, performed on the p-n-phenyls series and a typical mesogenic molecule (5CB). The model is constructed by connecting an array of anisotropic Gay-Berne sites and a collection of isotropic Lennard-Jones sites. The former mimics the rigid planar six-membered rings of the molecule, while the latter represents the flexible chain, if present. Such intermolecular potential, coupled with an intramolecular part to account for molecular flexibility, is parametrized from ab initio information only, obtained through the recently proposed Fragmentation-Reconstruction Method (FRM). Computer simulations are performed on all systems by exploring phase behavior at several temperatures and by comparing the resulting thermodynamic and structural properties with the relevant experimental data. Despite the simplicity of the present models, the good agreement with the experimental measures suggests the possibility of adopting such hybrid potentials for those systems with a large number of atoms, where high computational cost does not allow the use of more accurate atomistic potentials.