Molecular Dynamics Simulation of Lipid-Modified Signaling Proteins.

Coarse-grained (CG) molecular dynamics (MD) simulations are performed to study the insertion of cyclic peptide nanotubes into cell membranes and to examine whether cyclic peptide nanotubes can function as an ion channel and thereby as an antibacterial agent. To do so, the two coarse-grained (CG) models for lipid molecules and for proteins developed by Marrink et al. (J. Phys. Chem. B 2004, 108, 750) and by Shih et al. (J. Phys. Chem. B 2006, 110, 3674), respectively, were extended and modified. These CG models were verified by performing CG MD and all-atom (AA) MD simulations for a cyclic peptide nanotube, 8 x cyclo[(-d-Ala-l-Glu-d-Ala-l-Gln-)2], in water and by comparing the results from the two simulations. Comparison between static and dynamic (water transport) properties obtained from both simulations shows good agreement. To study nanotube insertion, a CG cyclic peptide nanotube, 8 x cyclo[(-Trp-d-Leu-)4], was prepared above the surface of a CG DPPC lipid bilayer, restrained with constraints, and equilibrated, and then a series of CG MD simulations were carried out by lifting the constraints imposed on the nanotube. The CG MD simulations show that the cyclic peptide nanotube spontaneously inserts into and reorients inside the lipid bilayer. After insertion, the long axis of the cyclic peptide nanotube is aligned approximately perpendicular to the bilayer plane indicating that the nanotube can function as an ion channel and as an antibacterial agent. Tilt structures of the cyclic peptide nanotubes inside the lipid bilayer are found to be in agreement with experiment and earlier AA simulations. Lipid flip-flop, a migration of lipid molecules from one leaflet to the other leaflet of the lipid bilayer, is also observed from the CG MD simulations. Finally, the CG MD simulations reveal that a lipid headgroup can be inserted into the cyclic peptide nanotube. This process is confirmed by an AA MD simulation.

The Interaction of Phospholipase A2 with a Phospholipid Bilayer: Coarse-Grained Molecular Dynamics Simulations

Simple Method for Hybrid All-Atom and Coarse-Grained Molecular Dynamics Simulations and Its Applications

Two-pore channels (TPCs) constitute a family of intracellular cation channels with diverse permeation properties and functions in animals and plants. In the model plant Arabidopsis, the vacuolar cation channel TPC1 is involved in propagation of calcium waves and in cation homeostasis. Here, we discovered that the dimerization of a predicted helix within the carboxyl-terminus (CTH) is essential for the activity of TPC1. Bimolecular fluorescence complementation and co-immunoprecipitation demonstrated the interaction of the two C-termini and pointed towards the involvement of the CTH in this process. Synthetic CTH peptides dimerized with a dissociation constant of 3.9 µM. Disruption of this domain in TPC1 either by deletion or point mutations impeded the dimerization and cation transport. The homo-dimerization of the CTH was analyzed in silico using coarse-grained molecular dynamics (MD) simulations for the study of aggregation, followed by atomistic MD simulations. The simulations revealed that the helical region of the wild type, but not a mutated CTH forms a highly stable, antiparallel dimer with characteristics of a coiled-coil. We propose that the voltage- and Ca2+-sensitive conformation of TPC1 depends on C-terminal dimerization, adding an additional layer to the complex regulation of two-pore cation channels.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-016-2131-3) contains supplementary material, which is available to authorized users.

Interdiffusion of small molecules into a glassy polymer film via coarse-grained molecular dynamics simulations

DPPC-cholesterol phase diagram using coarse-grained Molecular Dynamics simulations

Molecular dynamics simulations of lipid-protein interactions in SLC4 proteins

We provide a critical assessment of explicit-solvent atomistic molecular dynamics (MD) simulations of RNA and protein/RNA complexes, written primarily for non-specialists with an emphasis to explain the limitations of MD. MD simulations can be likened to hypothetical single-molecule experiments starting from single atomistic conformations and investigating genuine thermal sampling of the biomolecules. The main advantage of MD is the unlimited temporal and spatial resolution of positions of all atoms in the simulated systems. Fundamental limitations are the short physical time-scale of simulations, which can be partially alleviated by enhanced-sampling techniques, and the highly approximate atomistic force fields describing the simulated molecules. The applicability and present limitations of MD are demonstrated on studies of tetranucleotides, tetraloops, ribozymes, riboswitches and protein/RNA complexes. Wisely applied simulations respecting the approximations of the model can successfully complement structural and biochemical experiments. WIREs RNA 2017, 8:e1405. doi: 10.1002/wrna.1405 For further resources related to this article, please visit the WIREs website.

P-gp Lipid Uptake Pathways Determined by Coarse-Grain Molecular Dynamic Simulation

Mirrored continuum and molecular scale simulations of deflagration in a nano-slab of HMX

We present a computational framework that integrates coarse-grained (CG) molecular dynamics (MD) simulations and a data-driven machine-learning (ML) method to gain insights into the conformations of polymers in solutions. We employ this framework to study conformational transition of a model thermosensitive polymer, poly( N-isopropylacrylamide) (PNIPAM). Here, we have developed the first of its kind, a temperature-independent CG model of PNIPAM that can accurately predict its experimental lower critical solution temperature (LCST) while retaining the tacticity in the presence of an explicit water model. The CG model was extensively validated by performing CG MD simulations with different initial conformations, varying the radius of gyration of chain, the chain length, and the angle between the adjacent monomers of the initial configuration of PNIPAM (total simulation time = 90 μs). Moreover, for the first time, we utilize the nonmetric multidimensional scaling (NMDS) method, a data-driven ML approach, to gain further insights into the mechanisms and pathways of this coil-to-globule transition by analyzing CG MD simulation trajectories. NMDS analysis provides entirely new insights and shows multiple metastable states of PNIPAM during its coil-to-globule transition above the LCST.

We review our recent studies of rubber system using coarse-grained molecular dynamics (CGMD) simulation. The CGMD simulation is one of the powerful tools to clarify the molecular chain dynamics of the rubber material in the deformation process. In this review, we show two topics listed below; the stretching of the rubber material in which the cross-linker is included, and the chain dynamics near the filler. In the first topics, we observe the chain conformation in the stretching. In this process, we can obtain the one or two strong force line of bonds. This nature indicates that the deformation of the rubber takes place in non-affine process in the nano-scale. In the second topics, we study the molecular motion near the filler, so called in the bound rubber layer. We construct the two models; the grafting chain model and the adsorbed chain model. We observe the local mean square displacement and the local glass transition temperature. We can observe that the chain moves slowly near the filler due to the restriction of the grafting or due to the attractive interaction between filler and polymer.

Advances in coarse-grained molecular dynamics (CGMD) simulations have extended the use of computational studies on biological macromolecules and their complexes, as well as the interactions of membrane protein and lipid complexes at a reduced level of representation, allowing longer and larger molecular dynamics simulations. Here, we present a computational platform dedicated to the preparation, running, and analysis of CGMD simulations. The platform is built on a completely revisited version of our Martini coarsE gRained MembrAne proteIn Dynamics (MERMAID) web server, and it integrates this with other three dedicated services. In its current version, the platform expands the existing implementation of the Martini force field for membrane proteins to also allow the simulation of soluble proteins using the Martini and the SIRAH force fields. Moreover, it offers an automated protocol for carrying out the backmapping of the coarse-grained description of the system into an atomistic one.

In the present work we have studied the influence of surface-induced interphases on the properties of a cross-linked polymer adhesive by reactive molecular dynamics (RMD) simulations. Particular attention has been directed to segregation phenomena leading to changes in the interphase dimension. To investigate the present systems, we have extended a recently developed RMD method from a simple irreversible polymerization [J. Phys. Chem. B2010, 114, 13656] to a curing process in the presence of a planar surface with tunable adsorption characteristics. The RMD simulations have been performed in coarse grained (CG) resolution for the constituents and the surface layer. The reactive mixture contains so-called initiator beads with connectivity one, monomer beads with connectivity two, as well as linker beads with connectivity four which render possible the formation of percolating network structures. The RMD simulations are controlled by a capture radius which defines the influence sphere of the CG beads in the reactive processes and by a delay time between two connectivity altering steps. A number of reactive starting mixtures have been prepared to analyze mass density distributions, local mole fraction profiles, the bond orientation relative to the surface, as well as average chain lengths as a function of the separation from the surface. To estimate the influence of the tunable surface on the derived quantities, we have correlated RMD data derived in the presence of the surface with data from pure bulk simulations. Adsorption selectivity has been modeled via a preferential surface potential for one of the components. On the basis of calculated mole fractions, we have evaluated the excess chemical potential for the linkers at the surface by Boltzmann inversion. The extension of the density fluctuations is not changed in the transition from the starting mixture to the cured network. For other quantities different interphase properties are influenced by the type of the system (starting mixture, cured system) and by the surface potentials. The RMD results have been adopted to identify key parameters in curing processes that are influenced by an attractive surface.

Recent breakthroughs in neural network-based structure prediction methods, such as AlphaFold2 and RoseTTAFold, have dramatically improved the quality of computational protein structure prediction. These models also provide statistical confidence scores that can estimate uncertainties in the predicted structures, but it remains unclear to what extent these scores are related to the intrinsic conformational dynamics of proteins. Here, we compare AlphaFold2 prediction scores with explicit large-scale molecular dynamics simulations of 28 one- and two-domain proteins with varying degrees of flexibility. We demonstrate a strong correlation between the statistical prediction scores and the explicit motion derived from extensive atomistic molecular dynamics simulations and further derive an elastic network model based on the statistical scores of AlphFold2 (AF-ENM), which we benchmark in combination with coarse-grained molecular dynamics simulations. We show that our AF-ENM method reproduces the global protein dynamics with improved accuracy, providing a powerful way to derive effective molecular dynamics using neural network-based structure prediction models.