Interpretation of H-NMR Experiments on the Orientation of the Transmembrane Helix WALP23 by Computer Simulations

Orientation, dynamics, and packing of transmembrane helical peptides are important determinants of membrane protein structure, dynamics, and function. Because it is difficult to investigate these aspects by studying real membrane proteins, model transmembrane helical peptides are widely used. NMR experiments provide information on both orientation and dynamics of peptides, but they require that motional models be interpreted. Different motional models yield different interpretations of quadrupolar splittings (QS) in terms of helix orientation and dynamics. Here, we use coarse-grained (CG) molecular dynamics (MD) simulations to investigate the behavior of a well-known model transmembrane peptide, WALP23, under different hydrophobic matching/mismatching conditions. We compare experimental ²H-NMR QS (directly measured in experiments), as well as helix tilt angle and azimuthal rotation (not directly measured), with CG MD simulation results. For QS, the agreement is significantly better than previously obtained with atomistic simulations, indicating that equilibrium sampling is more important than atomistic details for reproducing experimental QS. Calculations of helix orientation confirm that the interpretation of QS depends on the motional model used. Our simulations suggest that WALP23 can form dimers, which are more stable in an antiparallel arrangement. The origin of the preference for the antiparallel orientation lies not only in electrostatic interactions but also in better surface complementarity. In most cases, a mixture of monomers and antiparallel dimers provides better agreement with NMR data compared to the monomer and the parallel dimer. CG MD simulations allow predictions of helix orientation and dynamics and interpretation of QS data without requiring any assumption about the motional model.     

Membrane Binding and Self-Association of the Epsin N-Terminal Homology Domain

Epsin possesses a conserved epsin N-terminal homology (ENTH) domain that acts as a phosphatidylinositol 4,5-bisphosphate‐lipid‐targeting and membrane‐curvature‐generating element. Upon binding phosphatidylinositol 4,5‐bisphosphate, the N-terminal helix (H₀) of the ENTH domain becomes structured and aids in the aggregation of ENTH domains, which results in extensive membrane remodeling. In this article, atomistic and coarse-grained (CG) molecular dynamics (MD) simulations are used to investigate the structure and the stability of ENTH domain aggregates on lipid bilayers. EPR experiments are also reported for systems composed of different ENTH-bound membrane morphologies, including membrane vesicles as well as preformed membrane tubules. The EPR data are used to help develop a molecular model of ENTH domain aggregates on preformed lipid tubules that are then studied by CG MD simulation. The combined computational and experimental approach suggests that ENTH domains exist predominantly as monomers on vesiculated structures, while ENTH domains self-associate into dimeric structures and even higher‐order oligomers on the membrane tubes. The results emphasize that the arrangement of ENTH domain aggregates depends strongly on whether the local membrane curvature is isotropic or anisotropic. The molecular mechanism of ENTH‐domain-induced membrane vesiculation and tubulation and the implications of the epsin's role in clathrin-mediated endocytosis resulting from the interplay between ENTH domain membrane binding and ENTH domain self-association are also discussed.     

REACH coarse-grained biomolecular simulation: transferability between different protein structural classes

Coarse graining of protein interactions provides a means of simulating large biological systems. The REACH (Realistic Extension Algorithm via Covariance Hessian) coarse-graining method, in which the force constants of a residue-scale elastic network model are calculated from the variance-covariance matrix obtained from atomistic molecular dynamics (MD) simulation, involves direct mapping between scales without the need for iterative optimization. Here, the transferability of the REACH force field is examined between protein molecules of different structural classes. As test cases, myoglobin (all α), plastocyanin (all β), and dihydrofolate reductase (α/β) are taken. The force constants derived are found to be closely similar in all three proteins. An MD version of REACH is presented, and low-temperature coarse-grained (CG) REACH MD simulations of the three proteins are compared with atomistic MD results. The mean-square fluctuations of the atomistic MD are well reproduced by the CGMD. Model functions for the CG interactions, derived by averaging over the three proteins, are also shown to produce fluctuations in good agreement with the atomistic MD. The results indicate that, similarly to the use of atomistic force fields, it is now possible to use a single, generic REACH force field for all protein studies, without having first to derive parameters from atomistic MD simulation for each individual system studied. The REACH method is thus likely to be a reliable way of determining spatiotemporal motion of a variety of proteins without the need for expensive computation of long atomistic MD simulations.     

Multiscale computer simulation of the immature HIV-1 virion

Multiscale computer simulations, employing a combination of experimental data and coarse-graining methods, are used to explore the structure of the immature HIV-1 virion. A coarse-grained (CG) representation is developed for the virion membrane shell and Gag polypeptides using molecular level information. Building on the results from electron cryotomography experiments, the simulations under certain conditions reveal the existence of an incomplete p6 hexameric lattice formed from hexameric bundles of the Gag CA domains. In particular, the formation and stability of the immature Gag lattice at the CG level requires enhanced interfacial interactions of the CA protein C-terminal domains (CTDs). An exact mapping of the CG representation back to the molecular level then allows for detailed atomistic molecular dynamics studies to confirm the existence of these enhanced CA_CTD interactions and to probe their possible origin. The multiscale simulations further provide insight into potential CA_CTD mutations that may disrupt or modify the Gag immature lattice assembly process in the immature HIV-1 virion.     

Minimised atomistic model and main evolution path for dominant B m I n clusters in boron diffusion

In this paper, we report our study on the minimised atomistic model (MAM) and the determination of an evolution path for dominant B _m I _n clusters during boron diffusion in kinetic Monte Carlo (KMC). It has been known that clusters generated after ion implantation play a decisive role in the enhanced boron diffusion at the tail region while being immobile at the peak region. Our MAM, based on the simple continuum model and the simple atomistic model, takes the smallest number of intermediate clusters into account as well as dominant clusters for the evolution path of interstitial clusters during boron diffusion. We find that intermediate clusters such as B₂I₃ and B₃I₃ play a significant role during the evolution of clusters despite the fact that the lifetimes of the corresponding intermediate clusters are relatively short due to low binding energies. Also, through our simulation results, we find the main evolution path of dominant clusters from B₂I to B₃I during thermal annealing in the MAM. Furthermore, our investigation reveals that the density of BI₂ clusters increases at the beginning of the annealing process while the density of B₃I increases at a later stage. KMC simulation results are compared with experimental SIMS data, which support our theoretical model.     

Molecular dynamics simulation on structural conformation of conjugated polymer-functionalised films for optimal fluorescent performance

The sensitive structure-related fluorescent properties of p-phenyleneethynylene (PPE)-functionalised fluorescent films with side chains and without side chains in different chemical environments are studied by molecular dynamics simulations. The calculations demonstrate that the structural change plays a crucial role in the fluorescent performance of PPE films, in which a major contribution is from the conformation of side chains. The PPE molecules with sides chains immobilised on SiO₂ substrate prefer to aggregate together in a dry state, but are more likely to stay in a monomolecular state in THF solvent. To an optimal concentration of the solvent molecules, the side chains are even perpendicular to the backbones of the molecules. The aggregation and separation of the PPE molecules with side chains are found to be controlled by the contraction and extension of the side chains connected to PPE. The van der Waals' force between the side chains is mainly responsible for these changes, which leads to a spreading out of the side chains in the presence of THF. All the results from the simulation studies can successfully explain the experimental observations.     

Comparing experimental and simulated pressure-area isotherms for DPPC

Although pressure-area isotherms are commonly measured for lipid monolayers, it is not always appreciated how much they can vary depending on experimental factors. Here, we compare experimental and simulated pressure-area isotherms for dipalmitoylphosphatidylcholine (DPPC) at temperatures ranging between 293.15 K and 323.15 K, and explore possible factors influencing the shape and position of the isotherms. Molecular dynamics simulations of DPPC monolayers using both coarse-grained (CG) and atomistic models yield results that are in rough agreement with some of the experimental isotherms, but with a steeper slope in the liquid-condensed region than seen experimentally and shifted to larger areas. The CG lipid model gives predictions that are very close to those of atomistic simulations, while greatly improving computational efficiency. There is much more variation among experimental isotherms than between isotherms obtained from CG simulations and from the most refined simulation available. Both atomistic and CG simulations yield liquid-condensed and liquid-expanded phase area compressibility moduli that are significantly larger than those typically measured experimentally, but compare well with some experimental values obtained under rapid compression.     

Coarse-Grained Molecular Models of Water: A Review

Coarse-grained (CG) models have proven to be very effective tools in the study of phenomena or systems that involve large time- and length-scales. By decreasing the degrees of freedom in the system and using softer interactions than seen in atomistic models, larger timesteps can be used and much longer simulation times can be studied. CG simulations are widely used to study systems of biological importance that are beyond the reach of atomistic simulation, necessitating a computationally efficient and accurate CG model for water. In this review, we discuss the methods used for developing CG water models and the relative advantages and disadvantages of the resulting models. In general, CG water models differ with regards to how many waters each CG group or bead represents, whether analytical or tabular potentials have been used to describe the interactions, and how the model incorporates electrostatic interactions. Finally, how the models are parameterized depends on their application, so, while some are fitted to experimental properties such as surface tension and density, others are fitted to radial distribution functions extracted from atomistic simulations.     

Structure-Based Simulations of the Translocation Mechanism of the Hepatitis C Virus NS3 Helicase along Single-Stranded Nucleic Acid

The NS3 helicase of Hepatitis C virus is an ATP-fueled molecular motor that can translocate along single-stranded (ss) nucleic acid, and unwind double-stranded nucleic acids. It makes a promising antiviral target and an important prototype system for helicase research. Despite recent progress, the detailed mechanism of NS3 helicase remains unknown. In this study, we have combined coarse-grained (CG) and atomistic simulations to probe the translocation mechanism of NS3 helicase along ssDNA. At the residue level of detail, our CG simulations have captured functionally important interdomain motions of NS3 helicase and reproduced single-base translocation of NS3 helicase along ssDNA in the 3′–5′ direction, which is in good agreement with experimental data and the inchworm model. By combining the CG simulations with residue-specific perturbations to protein-DNA interactions, we have identified a number of key residues important to the translocation machinery that agree with previous structural and mutational studies. Additionally, our atomistic simulations with targeted molecular dynamics have corroborated the findings of CG simulations and further revealed key protein-DNA hydrogen bonds that break/form during the transitions. This study offers, to our knowledge, the most detailed and realistic simulations of translocation mechanism of NS3 helicase. The simulation protocol established in this study will be useful for designing inhibitors that target the translocation machinery of NS3 helicase, and for simulations of a variety of nucleic-acid-based molecular motors.     

A systematic methodology for defining coarse-grained sites in large biomolecules

Coarse-grained (CG) models of biomolecules have recently attracted considerable interest because they enable the simulation of complex biological systems on length-scales and timescales that are inaccessible for atomistic molecular dynamics simulation. A CG model is defined by a map that transforms an atomically detailed configuration into a CG configuration. For CG models of relatively small biomolecules or in cases that the CG and all-atom models have similar resolution, the construction of this map is relatively straightforward and can be guided by chemical intuition. However, it is more challenging to construct a CG map when large and complex domains of biomolecules have to be represented by relatively few CG sites. This work introduces a new and systematic methodology called essential dynamics coarse-graining (ED-CG). This approach constructs a CG map of the primary sequence at a chosen resolution for an arbitrarily complex biomolecule. In particular, the resulting ED-CG method variationally determines the CG sites that reflect the essential dynamics characterized by principal component analysis of an atomistic molecular dynamics trajectory. Numerical calculations illustrate this approach for the HIV-1 CA protein dimer and ATP-bound G-actin. Importantly, since the CG sites are constructed from the primary sequence of the biomolecule, the resulting ED-CG model may be better suited to appropriately explore protein conformational space than those from other CG methods at the same degree of resolution.     

A combined experimental and computational study on the material properties of shape memory polyurethane

A type of shape memory polyurethane with 60 wt% hard segments (SMPU60) was prepared. Its material properties were tested by dynamic mechanical analysis (DMA) and Instron, and simulated using fully atomistic molecular dynamics (MD). The glass transition temperature (T _g) of SMPU60 determined by DMA is 316 K, which is slightly lower than that estimated through MD simulations (T _g = 328 K) , showing the calculated T _g is in good agreement with experimental data. A complex hydrogen bonding network was revealed with the calculation of radial distribution functions (RDFs). The C═O⋯H bond is the predominant hydrogen-bonding interaction. With increasing temperature, both the hydrogen bonding and the moduli decreased, and the dissociation of intermolecular hydrogen bonding induced the decrease of the moduli.     

Study of the Alzheimer's Aβ40 peptide in SDS micelles using molecular dynamics simulations

The interaction of the Alzheimer's amyloid beta peptide, Aβ40, with sodium dodecyl sulfate (SDS) micelles, together with the self-assembly of SDS molecules around the peptide from an initial random distribution were studied using atomistic and coarse-grained (CG) molecular dynamics simulations. In atomistic simulations, the peptide structure in the micelle was characterized by two helical regions connected through a short hinge. The initial structure of the system was shown to affect the simulation results. The atomistic self-assembly of SDS molecules resulted in a 38-molecule micelle around the peptide, along with some globules and individual molecules. Coarse-grained simulation results, however, did not show such a difference, and at the end of all CG simulations, a complete 60-molecule micelle was obtained, with the peptide located at the interface of the micelle with water. The obtained CG radial density profiles and SDS micelle size and shape properties were identical for all CG simulations.     

Simple atomistic modeling of dominant B m I n clusters in boron diffusion

In this paper, we present a simple atomistic model for describing the evolution of interstitial clusters during boron diffusion in kinetic Monte-Carlo (KMC) calculation. It has been known that clusters generated after ion implantation play a decisive role in the enhanced boron diffusion at the tail region while being immobile at the peak region. Our model, which is based on the simple continuum model, takes the intermediate clusters into account as well as dominant clusters for describing the evolutionary behavior of interstitial clusters during boron diffusion. We found that the intermediate clusters such as B₃I₃ and B₂I₃ play a significant role during the evolution of clusters despite the fact that the lifetimes of the corresponding intermediate clusters are relatively short due to low binding energies. Further, our investigation revealed that B₃I is the most dominant cluster after annealing. We applied our simple atomistic model to the study of boron retardation in arsenic pre-doped substrate. KMC simulation results were compared with experimental SIMS data, which supports our theoretical model.     

Function and organization of Photosystem I polypeptides

Photosystem I functions as a plastocyanin:ferredoxin oxidoreductase in the thylakoid membranes of chloroplasts and cyanobacteria. The PS I complex contains the photosynthetic pigments, the reaction center P700, and five electron transfer centers (A₀, A₁, F_X, F_A, and F_B) that are bound to the PsaA, PsaB, and PsaC proteins. In addition, PS I complex contains at least eight other polypeptides that are accessory in their functions. Recent use of cyanobacterial molecular genetics has revealed functions of the accessory subunits of PS I. Site-directed mutagenesis is now being used to explore structure-function relations in PS I. The overall architecture of PSI complex has been revealed by X-ray crystallography, electron microscopy, and biochemical methods. The information obtained by different techniques can be used to propose a model for the organization of PS I. Spectroscopic and molecular genetic techniques have deciphered interaction of PS I proteins with the soluble electron transfer partners. This review focuses on the recent structural, biochemical and molecular genetic studies that decipher topology and functions of PS I proteins, and their interactions with soluble electron carriers.Abbreviation NHS N-hydroxysuccinamide This review is dedicated to Prof. J. Philip Thornber, in whose laboratory PRC was introduced to the green world of chlorophyllproteins.     

Molecular dynamics simulations of excimer forming (+)-anti-BPDE-DNA adducts in aqueous solution

The chemical carcinogen (+)-anti BPDE preferentially binds covalently to the guanine base in the minor groove of DNA. Fluorescence spectroscopic studies have shown that the BPDE molecules bound to DNA can interact in their photo-excited state giving strong excimer fluorescence when bound to poly(dGdC) · poly(dGdC). It was suggested that the formation of such excited state complexes is most probable when the two (+)-anti-BPDE bind to guanines of adjacent base pairs on the two different strands of the DNA. In the present work a model for such an excimer forming DNA-BPDE double adduct system has been constructed and shown to be stable over a 300 ps molecular dynamics simulation in a water box. The model is a d(CG)₃ · d(CG)₃ molecule with two BPDE molecules bound to the guanines at the 4th position on each strand, located in the minor groove and each oriented towards the 5 end of the modified strand, respectively. The results of 300 ps MD simulation show that the two BPDE chromophores exhibited on the average a relative geometry favourable for excimer formation. The local structure at the adduct position was considerably distorted and the helix axis was bent. The modified bases were found to be paired through a stable single non-Watson Crick type of hydrogen bond. Correspondence to: A. Gräslund     

First Principles Modeling of Dissociative Adsorption at Crystal Surfaces: Hydrogen on Pt(111)

Multiscale simulation has the potential of becoming the new modeling paradigm in chemical sciences. An important class of multiscale models involves the mapping of a finer scale model into an approximate surface that is used by a coarser scale model. As a specific example of this class we present the case of the adsorption dynamics of diatomic molecules on single crystal catalyst surfaces. The prototype system studied is the dissociative adsorption of H₂ on Pt(111). The finer scale model consists of density functional theory (DFT) periodic slab calculations that provide a small dataset for training an atomistic scale potential energy surface. The coarser scale model uses a semi-classical molecular dynamics (MD) algorithm to obtain the sticking coefficient as a function of the incident energy. Comparison to experimental data and published simulation work is presented. Finally, major challenges in multiscale modeling of chemical reactivity in coupled DFT/MD simulations are discussed, specifically the need for a systematic method of assessing the accuracy of the coarse graining process.     

Acclimation of Photosystem 2 Function of Norway Spruce Induced during First Season under Elevated CO2 in Lamellar Domes

Since July 28^th, 1997 the two experimental mini-stands of young Norway spruce [Picea abies (L.) Karst.] have been grown in lamellar domes at ambient (AC) and elevated concentrations of CO₂ [EC, i.e., ambient + 350 µmol(CO₂) mol^–1]. Before the start of exposure to EC (June 1997) the dependencies of photosystem 2 (PS2) quantum yield (Y) on irradiance, estimating the efficiency of PPFD utilisation in PS2 photochemistry, were the same for AC and EC shoots. After one month of EC simulation (August 1997), Y values were higher for EC needles as compared with the AC ones (by 1–42 %), whereas two months later (October 1997) an opposite effect was observed (decrease of Y by from 1 to 33 %). By chlorophyll a (Chl a) fluorescence induction the effects of EC on PS2 function were further characterised. During the first month a moderate improvement of PS2 function was estimated for EC needles from slightly higher potential yield of PS2 photochemistry (F_V/F_M, by 1 %) and reduced amount of inactive PS2 reaction centres (relative F_p1 level, by 15 %). However, the prolonged exposure to EC led firstly to a slight but significant decrease of F_V/F_M (by 3 %), secondly to a reduction of half time of fluorescence rise (t_1/2, by 14 %), and finally to pronounced accumulation of inactive PS2 reaction centres (by 41 %). From the gradual response of individual Chl a fluorescence parameters we suggest a probable sequence of events determining the stimulation and subsequent depression of PS2 function for Norway spruce during the first season under EC.     

Multiscale modeling of cellular actin filaments: from atomistic molecular to coarse-grained dynamics

In this article, we present a computational multiscale model for the characterization of subcellular proteins. The model is encoded inside a simulation tool that builds coarse-grained (CG) force fields from atomistic simulations. Equilibrium molecular dynamics simulations on an all-atom model of the actin filament are performed. Then, using the statistical distribution of the distances between pairs of selected groups of atoms at the output of the MD simulations, the force field is parameterized using the Boltzmann inversion approach. This CG force field is further used to characterize the dynamics of the protein via Brownian dynamics simulations. This combination of methods into a single computational tool flow enables the simulation of actin filaments with length up to 400 nm, extending the time and length scales compared to state-of-the-art approaches. Moreover, the proposed multiscale modeling approach allows to investigate the relationship between atomistic structure and changes on the overall dynamics and mechanics of the filament and can be easily (i) extended to the characterization of other subcellular structures and (ii) used to investigate the cellular effects of molecular alterations due to pathological conditions.     

Coarse-Graining Provides Insights on the Essential Nature of Heterogeneity in Actin Filaments

Experiments have shown that actin is structurally polymorphic, but knowledge of the details of molecular level heterogeneity in both the dynamics of a single subunit and the interactions between subunits is still lacking. Here, using atomistic molecular dynamics simulations of the actin filament, we identify domains of atoms that move in a correlated fashion, quantify interactions between these domains using coarse-grained (CG) analysis methods, and perform CG simulations to explore the importance of filament heterogeneity. The persistence length and torsional stiffness calculated from molecular dynamics simulation data agree with experimental values. We additionally observe that distinct actin conformations coexist in actin filaments. The filaments also exhibit random twist angles that are broadly distributed. CG analysis reveals that interactions between equivalent CG pairs vary from one subunit to another. To explore the importance of heterogeneity on filament dynamics, we perform CG simulations using different methods of parameterization to show that only by including heterogeneous interactions can we reproduce the twist angles and related properties. Free energy calculations further suggest that in general the actin filament is best represented as a set of subunits with differing CG sites and interactions, and the incorporating heterogeneity into the CG interactions is more important than including that in the CG sites. Our work therefore presents a systematic method to explore molecular level detail in this large and complex biopolymer.     

A multiscale coarse-grained model of the SARS-CoV-2 virion

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Computer simulations of complete viral particles can provide theoretical insights into large-scale viral processes including assembly, budding, egress, entry, and fusion. Detailed atomistic simulations are constrained to shorter timescales and require billion-atom simulations for these processes. Here, we report the current status and ongoing development of a largely “bottom-up” coarse-grained (CG) model of the SARS-CoV-2 virion. Data from a combination of cryo-electron microscopy (cryo-EM), x-ray crystallography, and computational predictions were used to build molecular models of structural SARS-CoV-2 proteins, which were then assembled into a complete virion model. We describe how CG molecular interactions can be derived from all-atom simulations, how viral behavior difficult to capture in atomistic simulations can be incorporated into the CG models, and how the CG models can be iteratively improved as new data become publicly available. Our initial CG model and the detailed methods presented are intended to serve as a resource for researchers working on COVID-19 who are interested in performing multiscale simulations of the SARS-CoV-2 virion.