All-atom Research Articles

Curvature induction and sensing of the F-BAR protein Pacsin1 on lipid membranes via molecular dynamics simulations

F-Bin/Amphiphysin/Rvs (F-BAR) domain proteins play essential roles in biological processes that involve membrane remodelling, such as endocytosis and exocytosis. It has been shown that such proteins transform the lipid membrane into tubes. Notably, Pacsin1 from the Pacsin/Syndapin subfamily has the ability to transform the membrane into various morphologies: striated tubes, featureless wide and thin tubes, and pearling vesicles. The molecular mechanism of this interesting ability remains elusive. In this study, we performed all-atom (AA) and coarse-grained (CG) molecular dynamics simulations to investigate the curvature induction and sensing mechanisms of Pacsin1 on a membrane. From AA simulations, we show that Pacsin1 has internal structural flexibility. In CG simulations with parameters tuned from the AA simulations, spontaneous assembly of two Pacsin1 dimers through lateral interaction is observed. Based on the complex structure, we show that the regularly assembled Pacsin1 dimers bend a tensionless membrane. We also show that a single Pacsin1 dimer senses the membrane curvature, binding to a buckled membrane with a preferred curvature. These results provide molecular insights into polymorphic membrane remodelling.

Effects of Ether Linkage on Membrane Dipole Potential and Cholesterol Flip-Flop Motion in Lipid Bilayer Membranes.

In our previous work, we investigated the effect of ether linkage on the physical properties of lipid bilayers using all-atom (AA) simulations with different water models. However, the influence of ether linkage on the transportation of cholesterol in lipid bilayers is less well studied. In order to reduce computational costs in simulations at large time and length scales, we present coarse-grained (CG) simulations of diphytanyl phosphatidylcholine (ether-DPhPC) and diphytanoyl phosphatidylcholine (ester-DPhPC) bilayer membranes in this work. First, the CG and AA simulations consistently show that the substitution of ether linkage for ester linkage would prevent the penetration of water into the lipid bilayer membranes. Second, it is encouraging that the CG simulations can nicely capture the ether effect on membrane dipole potential, showing that the ether substitution for ester would significantly decrease the dipole potential. In particular, the CG results agree with the AA simulation results, revealing that the change in the dipole potential is accompanied with the alteration in the orientation of linkage group. Finally, we carried out 60 μs CG simulations of ether-DPhPC and ester-DPhPC bilayers at two cholesterol concentrations (10 and 40% mole fraction, respectively), showing that the ether substitution for ester would facilitate the cholesterol flip-flop motion in lipid bilayer membranes.

(Invited) Multiscale Molecular Modeling for Polymer Electrolyte Membrane for Fuel Cell

Multi-scale “molecular” modeling approach has been developed and applied to polymer electrolyte membrane. The goal of this work is to investigate the possible morphology, structure, dynamics, and mechanical properties of perfluorosulfonic acid (PFSA) membrane with realistic polymer chain lengths (>100 monomer units) by molecular dynamics (MD) simulations. First, we have carried out a series of all-atom (AA) MD simulations of PFSA polymer with a short chain length (10 monomer units) to yield reference structural data for building a coarse-grained (CG) molecular model. Although many phenomenological modeling based on dissipative particle dynamics has been proposed previously, a chemically accurate CG model should be beneficial to investigate the morphology in realistic membranes and to provide a concrete molecular design. Thus, we attempted to construct a predictive CG model for the structure and morphology of PFSA membranes that is compatible with the SDK CG water model. [1] As a first trial, we extended the parameter set in the SDK CG force field to examine a hydrated PFSA membrane based on thermodynamic and structural data from experiments and AA-MD simulations. However, a noticeable degradation of the morphology was detected, which motivated us to improve the structural properties by a combination with the iterative Boltzmann inversion (IBI) approach. The hybrid SDK/IBI model was determined to reasonably reproduce both the thermodynamic and structural properties of the PFSA membrane for all examined water contents. [2] In addition, the obtained CG model demonstrated good transferability. Then, we used the CG-MD to simulate realistic long-chained (including more than 120 monomer units) PFSA membranes. We obtained successfully a well converged structure for this long-chained membrane system. We also developed a reverse-mapping method and successfully used it to produce a well-equilibrated structure at all-atom resolution. We further investigated the mechanical properties of this realistic PSFA membranes at AA resolution. The uniaxial tension tests were conducted to understand the mechanical behavior of hydrated PEM membranes, especially the failure mechanism of the membranes. It was observed that the results (Poisson's ratio, free volume) of the uniaxial deformation were sensitive to the hydration level. This computational methodology will provide more chemically realistic predictions of the PEM membrane properties and give an insight into how to develop the large-scale atomistic PEM model in a multi-scale framework. We will further discuss the effect of equivalent weight (EW) and side chain length on morphology and dynamics of PFSA membranes.[3,4][1] Shinoda et al., Mol. Simul. 33, 27 (2007).[2] Kuo et al., J. Chem. Phys. 147, 094904 (2017).[3] Kuo et al., J. Phys. Chem. C 120, 25832 (2016).[4] Kuo et al., Polymer, 146, 53 (2018).

Backmapping from Multiresolution Coarse-Grained Models to Atomic Structures of Large Biomolecules by Restrained Molecular Dynamics Simulations Using Bayesian Inference.

Coarse-grained (CG) simulations have allowed access to larger length scales and longer time scales in the study of the dynamic processes of large biomolecules than all-atom (AA) molecular dynamics (MD) simulations. Backmapping from CG models to AA structures has long been studied because it enables us to gain detailed structure insights from CG simulations. Many methods first construct an AA structure from the CG model by fragments, random placement, or geometrical rules and subsequently optimize the solution via energy minimization, simulated annealing or position-restrained simulations. However, such methods may only work well on residue-level CG models and cannot consider the deviations of CG models. In this work, we describe, to the best of our knowledge, a new backmapping method based on Bayesian inference and restrained MD simulations. Restraints with log harmonic energy terms are defined according to the target CG model using the Bayesian inference in which the CG deviations can be estimated. From an initial AA structure obtained from either high-resolution experiments or homology modeling, a MD simulation with the aforementioned restraints is performed to obtain a final AA structure that is a backmapping of the target CG model. The method was validated using multiresolution CG models of the soluble extracellular region of the human epidermal growth factor receptor and was further applied to construct AA structures from CG simulations of the nucleosome core particle. The results demonstrate that our method can generate accurate AA structures of different types of biomolecules from multiple CG models with either residue-level resolution or much lower resolution than one-site-per-residue.

A Role for Lipid-Lipid Interactions in Vitamin E's Function as a Membrane Antioxidant

Vitamin E (α-tocopherol) is the principle lipid soluble antioxidant in cell membranes. Its purpose is to protect membrane lipids from oxidative damage. Whether unequal affinity for different lipids optimizes the proximity of vitamin E to polyunsaturated phospholipids, the lipid species most susceptible to oxidation, is the question that we address with MD simulations on lipid bilayers. Our studies suggest cholesterol, ubiquitous in the cell membranes of animals, excludes vitamin E from saturated raft-like domains enriched in the sterol. Preferential affinity for polyunsaturated phospholipids is not indicated - vitamin E, like polyunsaturated phospholipids, is pushed towards non-raft regions depleted in cholesterol. The binding energy measured for vitamin E in umbrella sampling AA (all-atom) simulations is greater for SM (sphingomyelin) than PDPC (1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine). Adding cholesterol to SM eliminates the differential in binding energy. CG (coarse-grained) simulations run on PDPC/SM/cholesterol mixtures in the presence of vitamin E indicate the vitamin locates at the boundary between SM-rich/sterol-rich (raft-like) and PDPC-rich/sterol-poor (non-raft) domains. CG simulations run on mixtures replacing PDPC by DDPC (1,2-didocosahexanoyl-sn-glycero-3-phosphocholine) will reveal details of the molecular interactions of vitamin E at the distinct boundary between raft-like and non-raft domains that forms with the di-polyunsaturated phospholipid. The results of these studies will be presented.

Curvature effect and stabilize ruptured membrane of BAX derived peptide studied by molecular dynamics simulations

BAX protein plays a key role in mitochondrial membrane permeabilization and cytochrome c release upon apoptosis. The C-terminal transmembrane domain (TMD) of BAX is supposed to act a membrane anchor when BAX is activated leading to programmed cell death. Previous studies indicate that the C-terminal transmembrane domain of BAX mediates membrane disruption and pore formation, however, the mechanism of the membrane disruption and pore-forming capability of BAX C-terminal transmembrane domain still unclear. Here, we performed all-atom (AA) molecular dynamics simulations to study the membrane effect of TMD peptide. We also conducted coarse-grained (CG) molecular dynamics simulations to study the membrane curvature and the stabilization of ruptured membrane pores effect of TMD peptides. Our results indicated that TMD peptide decreases the local POPC lipids order. The membrane binding of TMD induced a positive membrane curvature, moreover, certain numbers of TMD could stabilize ruptured membrane pore in both CG and AA simulations. These results provide insight into the structure details of membrane pore formation by TMD peptides. The diameters of the pore are qualitatively in good agreement with available experimental data.

Effects of interface properties on the mechanical properties of bio-inspired cellulose nanocrystal (CNC)-based materials

Cellulose nanocrystals (CNCs) is a new family of cellulose materials with outstanding mechanical and chemical properties that have been successfully demonstrated to have potential for many applications. Understanding the mechanical behavior of individual CNCs and their interaction at nanoscale is very important for improving the manufacturing process and mechanical performance of the resulting materials at macroscale. However, due to time and length scale limitations for both, experimental observations and atomistic modeling, predicting the mechanical performance of a system consisting of many CNCs is still challenging. We present a coarse-grained model of CNCs based on both mechanical properties and crystal-crystal interactions to overcome this limitation. Parametrization of the model is carried out in comparison with all-atom (AA) molecular dynamics and experimental results of some specific mechanical and interfacial tests. Subsequently, verification is done with other independent tests. In particular, we note that the parameters of the model can be calibrated to capture the properties of both twisted and untwisted CNC interface without sacrificing the mechanical properties of the individual particle. Finally, we analyze the effect of interface properties on the mechanical performance of CNC-based materials including, bending test of a crystalline bundle, tensile test and fracture in two representative bioinspired architectures. The results revealed different failure mechanisms depending upon the interfacial configuration. For instance, well-aligned CNCs lead to a more brittle and catastrophic failure mechanism, whereas naturally twisted interfaces promote toughening mechanisms that helps attained optimal mechanical performance.

On the Structure Factors of Aqueous Mixtures of 1‐Propanol and 2‐Propanol: X‐Ray Diffraction Experiments and Molecular Dynamics Simulations

The structure factor of pure 1‐propanol, 2‐propanol, and mixtures of 1‐propanol/water and 2‐propanol/water, as a function of composition, has been determined experimentally and by molecular dynamics simulations. The primary aim is to find interatomic potentials that reproduce measured structural data at the highest possible level. For this reason, various alcohol potential models have been employed, including united atom (UA) and all atom (AA) types, in combination with a TIP4P‐based model for water. In order to improve agreement with experimental values of the dielectric constant and mass density, a new UA force field for the alcohols has also been constructed. In terms of structural properties, the AA model reproduces experimental results better than any of the UA models for all compositions.

Capturing Phase Behavior of Ternary Lipid Mixtures with a Refined Martini Coarse-Grained Force Field.

Whether lipid rafts are presentin the membranes of living cells remains hotly disputed despite their incontrovertible existence in liposomes at 298 K. In attempts to resolve this debate, molecular dynamics (MD) simulations have been extensively used to study lipid phase separation at high resolution. However, computation has been of limited utility in this respect because the experimental distributions of phases in lamellar lipid mixtures are poorly reproduced by simulations. In particular, all-atom (AA) approaches suffer from restrictions on accessible time scales and system sizes whereas the more efficient coarse-grained (CG) force fields remain insufficiently accurate to achieve correspondence with experiment. In this work, we refine the CG Martini parameters for the high- and low-melting temperature ( Tm) lipids 1,2-dipalmitoyl- sn-glycero-3-phosphatidylcholine (DPPC) and 1,2-dioleoyl- sn-glycero-3-phosphatidylcholine (DOPC). Our approach involves the modification of bonded Martini parameters based on fitting to atomistic simulations conducted with the CHARMM36 lipid force field. The resulting CG parameters reproduce experimental structural and thermodynamic properties of homogeneous lipid membranes while concurrently improving simulation fidelity to experimental phase diagrams of DPPC, DOPC, and cholesterol lipid mixtures. Importantly, the refined parameters provide much better phase accuracy for regions near the critical point that mimic the lipid concentrations under physiological conditions.

Coarse-graining models for molecular dynamics simulations of FCC metals

In this paper, four coarse-graining (CG) models are proposed to accelerate molecular dynamics simulations of FCC metals. To this aim, at first, a proper map between beads of the CG models and atoms of the all-atom (AA) system is assigned, afterwards mass of the beads and the parameters of the CG models are determined in a manner that the CG models and the original all-atom model have the same physical properties. To evaluate and compare precision of these four CG models, different static and dynamic simulations are conducted. The results show that these CG models are at least 4 times faster than the AA model, while their errors are less than 1 percent.

Energy Renormalization Method for the Coarse-Graining of Polymer Viscoelasticity.

Developing temperature transferable coarse-grained (CG) models is essential for the computational prediction of polymeric glass-forming (GF) material behavior, but their dynamics are often greatly altered from those of all-atom (AA) models mainly because of the reduced fluid configurational entropy under coarse-graining. To address this issue, we have recently introduced an energy renormalization (ER) strategy that corrects the activation free energy of the CG polymer model by renormalizing the cohesive interaction strength ε as a function of temperature T, i.e., ε(T), thus semiempirically preserving the T-dependent dynamics of the AA model. Here we apply our ER method to consider-in addition to T-dependency-the frequency f-dependent polymer viscoelasticity. Through smallamplitude oscillatory shear molecular dynamics simulations, we show that changing the imposed oscillation f on the CG systems requires changes in ε values (i.e., ε(T, f)) to reproduce the AA viscoelasticity. By accounting for the dynamic fragility of polymers as a material parameter, we are able to predict ε(T, f) under coarse-graining in order to capture the AA viscoelasticity, and consequently the activation energy, across a wide range of T and f in the GF regime. Specifically, we showcase our achievements on two representative polymers of distinct fragilities, polybutadiene (PB) and polystyrene (PS), and show that our CG models are able to sample viscoelasticity up to the megahertz regime, which approaches state-of-the-art experimental resolutions, and capture results sampled via AA simulations and prior experiments.

Persistence Length, End-to-End Distance, and Structure of Coarse-Grained Polymers.

Coarse-grained (CG) polymer simulations can access longer times and larger lengths than all-atom (AA) molecular dynamics simulations; however, not all CG models correctly reproduce polymer properties on all length scales. Here we coarse-grain atomistic position data from polyethylene (PE) and polytetrafluoroethylene (PTFE) melt simulations by combining λ backbone carbon atoms in a single CG bead. Resulting CG variables have correlations along the chain backbone that depend on the coarse-graining scale λ and are generally not reproduced by independent bond-length, bond-angle and torsion-angle distributions. By constructing distributions of CG variables equivalent to those from simulated CG potentials we are able to evaluate the bond-orientation correlation for different CG models at reduced computational cost. CG models and potentials that include only nonbonded, bond-length, and bond-angle interactions computed by Boltzmann inversion correctly reproduce the CG variable distributions but do not necessarily reproduce the chain stiffness, overestimating the persistence length Lp and end-to-end distance ⟨ R2⟩1/2 with increasing λ. While CG models that include an independent torsion angle match the bond-orientation correlation and ⟨ R2⟩1/2 better, only approximate models that include correlations between bond and torsion angles match the true bond-orientation correlation.

Multiscale Simulation of Protein Hydration Using the SWINGER Dynamical Clustering Algorithm.

To perform computationally efficient concurrent multiscale simulations of biological macromolecules in solution, where the all-atom (AT) models are coupled to supramolecular coarse-grained (SCG) solvent models, previous studies resorted to modified AT water models, such as the bundled-simple point charge (SPC) models, that use semiharmonic springs to restrict the relative movement of water molecules within a cluster. Those models can have a significant impact on the simulated biomolecules and can lead, for example, to a partial unfolding of a protein. In this work, we employ the recently developed alternative approach with a dynamical clustering algorithm, SWINGER, which enables a direct coupling of original unmodified AT and SCG water models. We perform an adaptive resolution molecular dynamics simulation of a Trp-Cage miniprotein in multiscale water, where the standard SPC water model is interfaced with the widely used MARTINI SCG model, and demonstrate that, compared to the corresponding full-blown AT simulations, the structural and dynamic properties of the solvated protein and surrounding solvent are well reproduced by our approach.

Reconstruction of Atomistic Structures from Coarse-Grained Models for Protein-DNA Complexes.

While coarse-grained (CG) simulations have widely been used to accelerate structure sampling of large biomolecular complexes, they are unavoidably less accurate and thus the reconstruction of all-atom (AA) structures and the subsequent refinement is desirable. In this study we developed an efficient method to reconstruct AA structures from sampled CG protein-DNA complex models, which attempts to model the protein-DNA interface accurately. First we developed a method to reconstruct atomic details of DNA structures from a three-site per nucleotide CG model, which uses a DNA fragment library. Next, for the protein-DNA interface, we referred to the side chain orientations in the known structure of the target interface when available. The other parts are modeled by existing tools. We confirmed the accuracy of the protocol in various aspects including the structure deviation in the self-reproduction, the base pair reproducibility, atomic contacts at the protein-DNA interface, and feasibility of the posterior AA simulations.

A Multi-Scale Model for Insulin Self-Association Rates and Oligomerization Kinetics

Insulin, a therapeutic protein, can aggregate during manufacture and is considered detrimental to its quality. Early identification of aggregation inducing factors would be an essential aspect concerning the design of mitigation strategies during manufacturing processes. The time-scales and length-scales relevant for aggregation makes the use of all-atom (AA) explicit solvent simulations for prediction of aggregation thermodynamics and/or kinetics very difficult. Since aggregation is mainly driven by non-native interactions, we have used the physics based MARTINI coarse grained model to model protein-protein interactions. In an earlier work we had identified aggregation-prone, partially folded intermediates (PFIs) of insulin. Here we have employed a transient-complex model to determine self-association rate of native insulin (N) and the PFIs of insulin. To this end, a set of most probable conformations of the N-PFI complex were first obtained using docking and scoring on basis of MMPBSA energies. These docked complexes were then refined by separating the N and PFI monomers translationally followed by long molecular dynamics simulations. In two sets of test cases we show that the binding interface of the final N-PFI complex is similar in both the AA simulations and CG-MARTINI simulations with elastic network constraints. We hypothesize that this N-PFI complex can be taken as the diffusion limited transient state for the insulin homodimer on aggregation pathway. We use the TransComp server to calculate association rates for formation of this diffusion limited complex. The dimer association rates and monomer conformational transition rates are used to determine all the rates for formation of various small oligomeric species on insulin aggregation pathway. These rates are then input to a kinetic monte carlo (KMC) scheme to determine oligomerization kinetics of insulin.

Rigid Rod Model for the Disordered Domains of Ribosomal Stalk Proteins P1P2

In eukaryotes, the ribosomal stalk proteins, which are responsible for the recruitment of transcription factors, consist of two P1P2 heterodimers attached onto one copy of P0. Recent NMR structure of full-length P1P2 reveals that their C-terminals are disordered in nature and can extend up to 125A away from the center of the heterodimer. Here, we report a rigid rod model aimed at sampling the structures of the disordered C-terminal tails of P1P2. With sequence-dependent angles and dihedrals, our model is constructed from all-atom (AA) molecular dynamics (MD) simulations of short P1P2 segments. Despite its apparent simplicity, the end-to-end distance and radius of gyration computed with our model are found to be in decent agreement with extensive AA simulations of the entire disordered C-terminals of P1P2. Using our model, we further investigate the experimentally observed correlation between the recruitment efficiency of the ribosome inactivating proteins and the length of P1P2 C-terminal tails. Overall, results of our calculation are in good agreement with experimental measurements based on truncation and insertion studies of P1P2, indicating that our rigid rod model offers an efficient and promising approach in structural and functional study of the disordered domains in the ribosome stalk proteins.

Reduced Point Charge Models of Proteins: Effect of Protein–Water Interactions in Molecular Dynamics Simulations of Ubiquitin Systems

We investigate the influence of various solvent models on the structural stability and protein-water interface of three ubiquitin complexes (PDB access codes: 1Q0W , 2MBB , 2G3Q ) modeled using the Amber99sb force field (FF) and two different point charge distributions. A previously developed reduced point charge model (RPCM), wherein each amino acid residue is described by a limited number of point charges, is tested and compared to its all-atom (AA) version. The complexes are solvated in TIP4P-Ew or TIP3P type water molecules, involving either the scaling of the Lennard-Jones protein-Owater interaction parameters, or the coarse-grain (CG) SIRAH water description. The best agreements between the RPCM and AA models were obtained for structural, protein-water, and ligand-ubiquitin properties when using the TIP4P-Ew water FF with a scaling factor γ of 0.7. At the RPCM level, a decrease in γ, or the inclusion of SIRAH particles, allows weakening of the protein-water interactions. It results in a slight collapse of the protein structure and a less compact hydration shell and, thus, in a decrease in the number of protein-water and water-water H-bonds. The dynamics of the surface protein atoms and of the water shell molecules are also slightly refrained, which allow the generation of stable RPCM trajectories.

Extending pressure-matching to inhomogeneous systems via local-density potentials.

Bottom-up coarse-grained models describe the intermolecular structure of all-atom (AA) models with desirable accuracy and efficiency. Unfortunately, structure-based models for liquids tend to dramatically overestimate the thermodynamic pressure and, consequently, tend to vaporize under ambient conditions. By employing a volume potential to introduce additional cohesion, self-consistent pressure-matching provides a simple and robust method for accurately reproducing the pressure equation of state (EoS) for homogeneous fluids, while still preserving an accurate description of intermolecular structure. Because they depend upon the global density, though, volume potentials cannot be directly employed for inhomogeneous systems, such as liquid-vapor interfaces. In the present work, we demonstrate that volume potentials can be readily adapted as potentials of the local density. The resulting local-density potentials provide an accurate description of the structure, pressure EoS, and local density fluctuations of an AA model for liquid methanol. Moreover, we demonstrate that very slight modifications to these local-density potentials allow for a quantitative description of either local or global density fluctuations. Most importantly, we demonstrate that the resulting potentials, which were parameterized to describe a homogeneous liquid, also generate stable liquid-vapor coexistence. However, further work is necessary to more accurately reproduce the interfacial density profile.

Effects of Coarse Graining and Saturation of Hydrocarbon Chains on Structure and Dynamics of Simulated Lipid Molecules

Molecular dynamics simulations are used extensively to study the processes on biological membranes. The simulations can be conducted at different levels of resolution: all atom (AA), where all atomistic details are provided; united atom (UA), where hydrogen atoms are treated inseparably of corresponding heavy atoms; and coarse grained (CG), where atoms are grouped into larger particles. Here, we study the behavior of model bilayers consisting of saturated and unsaturated lipids DOPC, SOPC, OSPC and DSPC in simulations performed using all atom CHARMM36 and coarse grained Martini force fields. Using principal components analysis, we show that the structural and dynamical properties of the lipids are similar, both in AA and CG simulations, although the unsaturated molecules are more dynamic and favor more extended conformations. We find that CG simulations capture 75 to 100% of the major collective motions, overestimate short range ordering, result in more flexible molecules and 5–7 fold faster sampling. We expect that the results reported here will be useful for comprehensive quantitative comparisons of simulations conducted at different resolution levels and for further development and improvement of CG force fields.

Role of Dynamic Heterogeneities in Ionic Liquids: Insights from All-Atom and Coarse-Grained Molecular Dynamics Simulation Studies.

We performed molecular dynamics simulations for the room-temperature ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6 ]). By employing all-atom (AA) and coarse-grained (CG) models, we compared the characteristic times of various dynamical modes, from vibration to diffusion, and the importance of dynamical heterogeneities at different levels of chemical resolution and over broad temperature ranges. It was shown that coarse graining leads to a substantial speedup in molecular dynamics, whereas it weakly affects the strength of dynamical heterogeneities. Despite the general speedup, several relationships between dynamical modes on different timescales were preserved. In particular, the heterogeneity timescales of the AA and CG models collapse onto the same curve as a function of the structural (α) relaxation time τα . Moreover, vibrational amplitudes and relaxation times τα are related at both levels of chemical resolution. We argue that the robustness of these relationships assists the development of dynamically consistent coarse-graining strategies and justifies the use of simplified models for a theoretical understanding of viscous liquids.