Conformational Energy Research Articles

Characterizing the Conformational Free-Energy Landscape of RNA Stem-Loops Using Single-Molecule Field-Effect Transistors.

We have developed and used single-molecule field-effect transistors (smFETs) to characterize the conformational free-energy landscape of RNA stem-loops. Stem-loops are one of the most common RNA structural motifs and serve as building blocks for the formation of complex RNA structures. Given their prevalence and integral role in RNA folding, the kinetics of stem-loop (un)folding has been extensively characterized using both experimental and computational approaches. Interestingly, these studies have reported vastly disparate timescales of (un)folding, which has been interpreted as evidence that (un)folding of even simple stem-loops occurs on a highly rugged conformational energy landscape. Because smFETs do not rely on fluorophore reporters of conformation or mechanical (un)folding forces, they provide a unique approach that has allowed us to directly monitor tens of thousands of (un)folding events of individual stem-loops at a 200 μs time resolution. Our results show that under our experimental conditions, stem-loops (un)fold over a 1-200 ms timescale during which they transition between ensembles of unfolded and folded conformations, the latter of which is composed of at least two sub-populations. The 1-200 ms timescale of (un)folding we observe here indicates that smFETs report on complete (un)folding trajectories in which unfolded conformations of the RNA spend long periods of time wandering the free-energy landscape before sampling one of several misfolded conformations or the natively folded conformation. Our findings highlight the extremely rugged landscape on which even the simplest RNA structural elements fold and demonstrate that smFETs are a unique and powerful approach for characterizing the conformational free-energy of RNA.

Design of a Fully Non‐Fused Bulk Heterojunction toward Efficient and Low‐Cost Organic Photovoltaics

AbstractTo modulate the miscibility between donor and acceptor materials both possessing fully non‐fused ring structures, a series of electron acceptors (A4T‐16, A4T‐31 and A4T‐32) with different polar functional substituents were synthesized and investigated. The three acceptors show good planarity, high conformational stability, complementary absorption and energy levels with the non‐fused polymer donor (PTVT‐BT). Among them, A4T‐32 possesses the strongest polar functional group and shows the highest surface energy, which facilitates morphological modulation in the bulk heterojunction (BHJ) blend. Benefiting from the proper morphology control method, an impressive power conversion efficiency (PCE) of approaching 16.0 % and a superior fill factor over 0.795 are achieved in the PTVT‐BT : A4T‐32‐based organic photovoltaic cells with superior photoactive materials price advantage, which represent the highest value for the cells based on the non‐fused blend films. Notably, this cell maintains ≈84 % of its initial PCE after nearly 2000 h under the continuous simulated 1‐sun‐illumination. In addition, the flexible PTVT‐BT : A4T‐32‐based cells were fabricated and delivered a decent PCE of 14.6 %. This work provides an effective molecular design strategy for the non‐fused non‐fullerene acceptors (NFAs) from the aspect of bulk morphology control in fully non‐fused BHJ layers, which is crucial for their practical applications.

Design of a Fully Non-Fused Bulk Heterojunction toward Efficient and Low-Cost Organic Photovoltaics.

To modulate the miscibility between donor and acceptor materials both possessing fully non-fused ring structures, a series of electron acceptors (A4T-16, A4T-31 and A4T-32) with different polar functional substituents were synthesized and investigated. The three acceptors show good planarity, high conformational stability, complementary absorption and energy levels with the non-fused polymer donor (PTVT-BT). Among them, A4T-32 possesses the strongest polar functional group and shows the highest surface energy, which facilitates morphological modulation in the bulk heterojunction (BHJ) blend. Benefiting from the proper morphology control method, an impressive power conversion efficiency (PCE) of approaching 16.0 % and a superior fill factor over 0.795 are achieved in the PTVT-BT : A4T-32-based organic photovoltaic cells with superior photoactive materials price advantage, which represent the highest value for the cells based on the non-fused blend films. Notably, this cell maintains ≈84 % of its initial PCE after nearly 2000 h under the continuous simulated 1-sun-illumination. In addition, the flexible PTVT-BT : A4T-32-based cells were fabricated and delivered a decent PCE of 14.6 %. This work provides an effective molecular design strategy for the non-fused non-fullerene acceptors (NFAs) from the aspect of bulk morphology control in fully non-fused BHJ layers, which is crucial for their practical applications.

Conformation and energy investigation of microtubule longitudinal dynamic instability induced by natural products.

The natural products plinabulin, docetaxel, and vinblastine are microtubule targeting agents (MTAs). They have been used alone or in combination in cancer treatment. However, the exact nature of their effects on microtubule (MT) polymerization dynamics is poorly understood. To elucidate the longitudinal conformational and energetic changes during MT dynamics, a total of 140 ns molecular dynamic simulations combined with binding free energy calculations were performed on seven tubulin models. The results indicated that the drugs disrupted MT polymerization by altering both MT conformation and binding free energy of the neighboring tubulin subunits. The combination of plinabulin and docetaxel destabilized MT polymerization due to bending MT and weakening the polarity of tubulin polymerization. The new combination of docetaxel and vinblastine synergistically enhanced MT depolymerization and bending, while plinabulin and vinblastine had no synergistic inhibitory effects. The results were verified by the tubulin assembly assay. Our study obtained a comprehensive understanding of the action mechanisms of three natural drugs and their combinations on MT dynamic, provided theoretical guidance for new MTA combinations, and would promote the optimal use of MTA and contribute to developing new MTAs as anticancer agents.

Performance of Localized-Orbital Coupled-Cluster Approaches for the Conformational Energies of Longer n-Alkane Chains.

We report an update and enhancement of the ACONFL (conformer energies of large alkanes [J. Phys. Chem. A2022,126, 3521-3535]) dataset. For the ACONF12 (n-dodecane) subset, we report basis set limit canonical coupled-cluster with singles, doubles, and perturbative triples [i.e., CCSD(T)] reference data obtained from the MP2-F12/cc-pV{T,Q}Z-F12 extrapolation, [CCSD(F12*)-MP2-F12]/aug-cc-pVTZ-F12, and a (T) correction from conventional CCSD(T)/aug-cc-pV{D,T}Z calculations. Then, we explored the performance of a variety of single and composite localized-orbital CCSD(T) approximations, ultimately finding an affordable localized natural orbital CCSD(T) [LNO-CCSD(T)]-based post-MP2 correction that agrees to 0.006 kcal/mol mean absolute deviation with the revised canonical reference data. In tandem with canonical MP2-F12 complete basis set extrapolation, this was then used to re-evaluate the ACONF16 and ACONF20 subsets for n-hexadecane and n-icosane, respectively. Combining those with the revised canonical reference data for the dodecane conformers (i.e., ACONF12 subset), a revised ACONFL set was obtained. It was then used to assess the performance of different localized-orbital coupled-cluster approaches, such as pair natural orbital localized CCSD(T) [PNO-LCCSD(T)] as implemented in MOLPRO, DLPNO-CCSD(T0) and DLPNO-CCSD(T1) as implemented in ORCA, and LNO-CCSD(T) as implemented in MRCC, at their respective "Normal", "Tight", "vTight", and "vvTight" accuracy settings. For a given accuracy threshold and basis set, DLPNO-CCSD(T1) and DLPNO-CCSD(T0) perform comparably. With "VeryTightPNO" cutoffs, explicitly correlated DLPNO-CCSD(T1)-F12/VDZ-F12 is the best pick among all the DLPNO-based methods tested. To isolate basis set incompleteness from localized-orbital-related truncation errors (domain, LNOs), we have also compared the localized coupled-cluster approaches with canonical DF-CCSD(T)/aug-cc-pVTZ for the ACONF12 set. We found that gradually tightening the cutoffs improves the performance of LNO-CCSD(T), and using a composite scheme such as vTight + 0.50[vTight - Tight] improves things further. For DLPNO-CCSD(T1), "TightPNO" and "VeryTightPNO" offer a statistically similar accuracy, which gets slightly better when TCutPNO is extrapolated to the complete PNO space limit. Similar to Brauer et al.'s [Phys. Chem. Chem. Phys.2016,18 (31), 20905-20925] previous report for the S66x8 noncovalent interactions, the dispersion-corrected direct random phase approximation (dRPA)-based double hybrids perform remarkably well for the ACONFL set. While the revised reference data do not affect any conclusions on the less accurate methods, they may upend orderings for more accurate methods with error statistics on the same order as the difference between reference datasets.

An Efficient Approach to Large-Scale Ab Initio Conformational Energy Profiles of Small Molecules.

Accurate conformational energetics of molecules are of great significance to understand maby chemical properties. They are also fundamental for high-quality parameterization of force fields. Traditionally, accurate conformational profiles are obtained with density functional theory (DFT) methods. However, obtaining a reliable energy profile can be time-consuming when the molecular sizes are relatively large or when there are many molecules of interest. Furthermore, incorporation of data-driven deep learning methods into force field development has great requirements for high-quality geometry and energy data. To this end, we compared several possible alternatives to the traditional DFT methods for conformational scans, including the semi-empirical method GFN2-xTB and the neural network potential ANI-2x. It was found that a sequential protocol of geometry optimization with the semi-empirical method and single-point energy calculation with high-level DFT methods can provide satisfactory conformational energy profiles hundreds of times faster in terms of optimization.

Collaborative Assessment of Molecular Geometries and Energies from the Open Force Field.

Force fields form the basis for classical molecular simulations, and their accuracy is crucial for the quality of, for instance, protein-ligand binding simulations in drug discovery. The huge diversity of small-molecule chemistry makes it a challenge to build and parameterize a suitable force field. The Open Force Field Initiative is a combined industry and academic consortium developing a state-of-the-art small-molecule force field. In this report, industry members of the consortium worked together to objectively evaluate the performance of the force fields (referred to here as OpenFF) produced by the initiative on a combined public and proprietary dataset of 19,653 relevant molecules selected from their internal research and compound collections. This evaluation was important because it was completely blind; at most partners, none of the molecules or data were used in force field development or testing prior to this work. We compare the Open Force Field "Sage" version 2.0.0 and "Parsley" version 1.3.0 with GAFF-2.11-AM1BCC, OPLS4, and SMIRNOFF99Frosst. We analyzed force-field-optimized geometries and conformer energies compared to reference quantum mechanical data. We show that OPLS4 performs best, and the latest Open Force Field release shows a clear improvement compared to its predecessors. The performance of established force fields such as GAFF-2.11 was generally worse. While OpenFF researchers were involved in building the benchmarking infrastructure used in this work, benchmarking was done entirely in-house within industrial organizations and the resulting assessment is reported here. This work assesses the force field performance using separate benchmarking steps, external datasets, and involving external research groups. This effort may also be unique in terms of the number of different industrial partners involved, with 10 different companies participating in the benchmark efforts.

Toward Reliable and Insightful Entropy Calculations on Flexible Molecules.

The absolute entropy of a flexible molecule can be approximated by the sum of a rigid-rotor-harmonic-oscillator (RRHO) entropy and a Gibbs-Shannon entropy associated to the Boltzmann distribution for the occupation of the conformational energy levels. Herein, we show that such partitioning, which has received renewed interest, leads to accurate entropies of single molecules of increasing size provided that the conformational part is estimated by means of a set of discretization and expansion techniques that are able to capture the significant correlation effects among the torsional motions. To ensure a reliable entropy estimation, we rely on extensive sampling as that produced by classical molecular dynamics simulations on the microsecond time scale, which is currently affordable for small- and medium-sized molecules. According to test calculations, the gas-phase entropy of simple organic molecules is predicted with a mean unsigned error of 0.9 cal/(mol K) when the RRHO entropies are computed at the B3LYP-D3/cc-pVTZ level. Remarkably, the same protocol gives small errors [<1 cal/(mol K)] for the extremely flexible linear alkane molecules (CnH2n+2, n = 14, 16, and 18). Similarly, we obtain well-converged entropies for a more challenging test of drug molecules, which exhibit more pronounced correlation effects. We also perform equivalent entropy calculations on a 76 amino acid protein, ubiquitin, by taking advantage of the cutoff-dependent formulation of an expansion technique (correlation-consistent multibody local approximation, CC-MLA), which incorporates genuine correlation effects among the neighboring dihedral angles. Moreover, we show that insightful descriptors of the coupled torsional motions can be obtained with the CC-MLA approach.

ЭКОЛОГИЧЕСКАЯ НИША КАК ПОТЕНЦИАЛЬНАЯ ЯМА, ОПРЕДЕЛЯЮЩАЯ СОБСТВЕННЫЕ ЗНАЧЕНИЯ ВОЛНОВОЙ ФУНКЦИИ ЖИВОГО

This workconsiders the possibility of an analog transition between the microcosm of quantum mechanics and the macrocosm of biology, where the most important process is the relationship of a biological species (BS) with its ecological niche (EN). In the first workpart the hypothesis is put forward, that the EN acts as an analogue of a potential well in quantum mechanics, which makes it possible to apply the tools of the latter. Then the stable BS state, as a system structure, corresponds to the eigenvalues of some wave function that oscillates in the EN (like an electron in an atom). At the same time, it is possible to distinguish the linear and nonlinear stages of these oscillations. The evolution nonlinear part, when the BS enters a chaotic stage of existence, can be determined by both external changes in the EN and internal causes at the genome level.The first reasons can be called Darwinian, the second — Lamarckian. In general, the BS eigenvalues are determined by boundary conditions (based on the Hutchinson cube): generalized the EN geometry and other environmental factors. It is shown how the basic concepts of quantum mechanics such as superposition, tunneling through a potential barrier, the Pauli principleare manifest themselves in biology. The latter corresponds to Gause's law in biology: only one species with certain ecological needs can live inside one ecological niche. In the second work part possible evolutionary correlation effects are discussed between the potential well, determined by the corresponding EN, and the potential well, which affects the conformational (energy) genome state of the BS. It is assumed that a change in the EN transforms the informational genome status through natural selection. On the other hand, and a change in the genome topology of the individuals can eventually to change the species whole and lead to the transformation of its niche.

Calculations of molecular properties of 2-(2'-hydroxyphenyl)benzoxazole by semi-empirical tight-binding methods

The semi-empirical tight-binding methods GFN1-xTB and GFN2-xTB are applied to calculations of structure, energy and normal vibrations of the molecule of 2-(2'-hydroxyphenyl)benzoxazole undergoing excited state intramolecular proton transfer. The results are compared with ones obtained by the density-functional tight-binding methods with hydrogen interaction corrections and density functional theory. The GFN2-xTB method is found to provide good correspondence to the results obtained by more accurate but much slower density functional theory method for geometrical parameters of hydrogen bond, relative energy of molecular conformations and potential energy surface.

Friends in need: How chaperonins recognize and remodel proteins that require folding assistance.

Chaperonins are biological nanomachines that help newly translated proteins to fold by rescuing them from kinetically trapped misfolded states. Protein folding assistance by the chaperonin machinery is obligatory in vivo for a subset of proteins in the bacterial proteome. Chaperonins are large oligomeric complexes, with unusual seven fold symmetry (group I) or eight/nine fold symmetry (group II), that form double-ring constructs, enclosing a central cavity that serves as the folding chamber. Dramatic large-scale conformational changes, that take place during ATP-driven cycles, allow chaperonins to bind misfolded proteins, encapsulate them into the expanded cavity and release them back into the cellular environment, regardless of whether they are folded or not. The theory associated with the iterative annealing mechanism, which incorporated the conformational free energy landscape description of protein folding, quantitatively explains most, if not all, the available data. Misfolded conformations are associated with low energy minima in a rugged energy landscape. Random disruptions of these low energy conformations result in higher free energy, less folded, conformations that can stochastically partition into the native state. Two distinct mechanisms of annealing action have been described. Group I chaperonins (GroEL homologues in eubacteria and endosymbiotic organelles), recognize a large number of misfolded proteins non-specifically and operate through highly coordinated cooperative motions. By contrast, the less well understood group II chaperonins (CCT in Eukarya and thermosome/TF55 in Archaea), assist a selected set of substrate proteins. Sequential conformational changes within a CCT ring are observed, perhaps promoting domain-by-domain substrate folding. Chaperonins are implicated in bacterial infection, autoimmune disease, as well as protein aggregation and degradation diseases. Understanding the chaperonin mechanism and the specific proteins they rescue during the cell cycle is important not only for the fundamental aspect of protein folding in the cellular environment, but also for effective therapeutic strategies.

Molecular Docking and Dynamics Simulation of Several Flavonoids Predict Cyanidin as an Effective Drug Candidate against SARS-CoV-2 Spike Protein.

The in silico method has provided a versatile process of developing lead compounds from a large database in a short duration. Therefore, it is imperative to look for vaccinations and medications that can stop the havoc caused by SARS-CoV-2. The spike protein of SARS-CoV-2 is required for the viral entry into the host cells, hence inhibiting the virus from fusing and infecting the host. This study determined the binding interactions of 36 flavonoids along with two FDA-approved drugs against the spike protein receptor-binding domain of SARS-CoV-2 through molecular docking and molecular dynamics (MD) simulations. In addition, the molecular mechanics generalized Born surface area (MM/GBSA) approach was used to calculate the binding-free energy (BFE). Flavonoids were selected based on their in vitro assays on SARS-CoV and SARS-CoV-2. Our pharmacokinetics study revealed that cyanidin showed good drug-likeness, fulfilled Lipinski's rule of five, and conferred favorable toxicity parameters. Furthermore, MD simulations showed that cyanidin interacts with spike protein and alters the conformation and binding-free energy suited. Finally, an in vitro assay indicated that about 50% reduction in the binding of hACE2 with S1-RBD in the presence of cyanidin-containing red grapes crude extract was achieved at approximately 1.25 mg/mL. Hence, cyanidin may be a promising adjuvant medication for the SARS-CoV-2 spike protein based on in silico and in vitro research.

Correcting π-delocalisation errors in conformational energies using density-corrected DFT, with application to crystal polymorphs

We consider several molecules characterised by π-electron conjugation whose extent changes along a flexible torsional coordinate, and which represent the monomer units of polymorphic molecular crystals. Delocalisation error in density functional theory (DFT) adversely impacts conformational energies in these species, overstabilising the conformation that maximises conjugation length and leading to incorrect relative energies for the corresponding crystal polymorphs. We demonstrate that density-corrected (DC-)DFT, in which a DFT exchange-correlation functional is evaluated using a Hartree–Fock density, significantly reduces these conformational energy errors. When DC-DFT monomer energies are used as a low-cost intramolecular correction to a periodic DFT calculation of the molecular crystal, the resulting relative polymorph energies are within 1 kJ/mol of benchmark results.

Screening of potential inhibitors targeting the main protease structure of SARS-CoV-2 via molecular docking.

The novel coronavirus disease (COVID-19) caused by SARS-CoV-2 virus spreads rapidly to become a global pandemic. Researchers have been working to develop specific drugs to treat COVID-19. The main protease (Mpro) of SARS-CoV-2 virus plays a pivotal role in mediating viral replication and transcription, which makes it a potential therapeutic drug target against COVID-19. In this study, a virtual drug screening method based on the Mpro structure (Protein Data Bank ID: 6LU7) was proposed, and 8,820 compounds collected from the DrugBank database were used for molecular docking and virtual screening. A data set containing 1,545 drug molecules, derived from compounds with a low binding free energy score in the docking experiment, was established. N-1H-Indazol-5-yl-2-(6-methylpyridin-2-yl)quinazolin-4-amine, ergotamine, antrafenine, dihydroergotamine, and phthalocyanine outperformed the other compounds in binding conformation and binding free energy over the N3 inhibitor in the crystal structure. The bioactivity and ADMET properties of these five compounds were further investigated. These experimental results for five compounds suggested that they were potential therapeutics to be developed for clinical trials. To further verify the results of molecular docking, we also carried out molecular dynamics (MD) simulations on the complexes formed by the five compounds and Mpro. The five complexes showed stable affinity in terms of root mean square distance (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and hydrogen bond. It was further confirmed that the five compounds had potential inhibitory effects on SARS-CoV-2 Mpro.

Orthogonal conformation regulation enables highly efficient phosphorescence emission in BODIPY-fluorene derivatives without heavy atoms

The BODIPY-Fluorene derivatives with an orthogonal conformation were prepared for the emission of efficient phosphorescence. The derivatives show visible light absorption (497–513 nm), high phosphorescence quantum efficiency (36.2%) and realize control of luminescence color from green to orange-red. Typical orthogonal conformation and smaller excited state (S1 and T4) energy gap (0.05 eV) are favorable for intersystem crossing (ISC) process. The calculation are carried out for rationalization between the photophysical properties and conformation of the BODIPY-Fluorene derivatives. We demonstrate that the conformational substitution positions and the distance between D-A are promising strategy to regulate the emission lifetime and quantum efficiency for BODIPY derivatives. Moreover, the ability to generate singlet oxygen was measured by photooxidation of 1,3-diphenylisobenzofuran (DPBF) by singlet oxygen (1O2) photosensitization. At the same time, the LED device displays bright orange-red emission. This work paves the way for further research into the design and application of such materials in advanced optics.

DFT Calculation for Newly Synthesized 2-Chloro-1-(3-methyl-3-mesityl-cyclobutyl)– ethanone

The synthesis of cyclobutane rings, particularly stereospecifically, poses significant challenges in synthetic chemistry due to the highly strained ring topologies. The cyclobutane-containing natural products are appealing targets for total synthesis due to their new chemical structures and exceptional biological activity. In this study, we have presented the synthesis and structure analysis of 2-chloro-1-(3-methyl-3-mesityl-cyclobutyl)–ethanone. The molecular elucidation was conducted by Fourier transform infrared (IR) and Nuclear magnetic spectroscopy (NMR). The I recording in 4000-500cm-1 was done in the potassium bromide solid phase, while the NMR for both Hydrogen and Carbon was done in the Dimethyl sulfoxide-6. Density functional theory (DFT) was used to stimulate and confirm the structure and molecular characterization. Using DFT/cc-pVDZ method to study various conformers of the compound and their minimum energies by the scanning potential energy surface. In addition, the molecular electrostatic potential map (MEP) and charge spreading have been plotted for the molecule to account for the chemical reactivity and site selectivity. Furthermore, the thermodynamic properties of the molecule have been studied. A good correlation was found between experimental and stimulation studies for Fourier transform infrared and Nuclear magnetic spectroscopy results. In the stimulation data, the conformer's energy differences were very small.

A-value revisited: ring flip energy of chair structures in halogenated cyclohexanes by quantum chemical methods

A-value is conventionally defined as the ring flip Gibbs energy of chair conformers in monosubstituted cyclohexanes. It is well accepted in organic chemistry as one of the proxies of steric hindrance of a substituent group with respect to hydrogen. In this paper, the ring flip energy of mono– and dihalogenated cyclohexanes was investigated by high-level quantum chemical methods. Satisfactory agreements between calculated values and published experimental values from NMR were established before extending the concept to ring flip energies of polyhalogenated cyclohexanes. We assessed the qualitative and quantitative accuracy of prediction of ring flip energies by A-values in two models: a simple and intuitive model based on linear combinations of A-values and a proposed extension of this model to include geminal substituent interactions. The simple model results in poor predictions of ring flip energy in polyhalogenated cyclohexanes, and the extended model provides only slight improvement. Our data suggests that simple linear combination of traditional or extended A-values may not be appropriate for the energy prediction of systems in this study.

Conformational energies of microsolvated Na+ clusters with protic and aprotic solvents from GFNn-xTB methods.

Performance of contemporary tight-binding semiempirical GFNn-xTB methods for the conformational energies of singly charged sodium clusters Na+ (S)n (n= 4-8) with 3 protic and 8 aprotic solvents is examined against the reference RI-MP2/CBS method. The median Pearson correlation coefficients of ρ= 0.84 (GFN2-xTB) and ρ= 0.82 (GFN1-xTB) do not give the clear preference to any tested approach. GFN1-xTB method demonstrates more stable performance than its GFN2-xTB successor with the average mean absolute errors (MAEs)/mean signed errors (MSEs) of 1.2/0.2 and 2.3/1.6kcal mol-1 , respectively. Conformational energies produced by the computationally efficient DFT functional PBE and double-ζ basis set complemented with -D3(BJ) dispersion correction are suitable for the preliminary sampling (median ρ= 0.93), but should be used with a caution for the calculations of the average ensemble properties (MAE/MSE=1.7/1.1kcal mol-1 ). Higher-ranking PBE0-D3(BJ) and ωB97M-V with triple-ζ basis sets yield significantly lower MAEs/MSEs of 0.55/0.20 and 0.51/0.23 kcal mol-1 , respectively.

Multiscale Modeling of Hepatitis B Virus Capsid Assembly and Its Dimorphism.

Hepatitis B virus (HBV) is an endemic, chronic virus that leads to 800000 deaths per year. Central to the HBV lifecycle, the viral core has a protein capsid assembled from many copies of a single protein. The capsid protein adopts different (quasi-equivalent) conformations to form icosahedral capsids containing 180 or 240 proteins: T = 3 or T = 4, respectively, in Caspar-Klug nomenclature. HBV capsid assembly has become an important target for recently developed antivirals; nonetheless, the assembly pathways and mechanisms that control HBV dimorphism remain unclear. We describe computer simulations of the HBV assembly, using a coarse-grained model that has parameters learned from all-atom molecular dynamics simulations of a complete HBV capsid and yet is computationally tractable. Dynamical simulations with the resulting model reproduce experimental observations of HBV assembly pathways and products. By constructing Markov state models and employing transition path theory, we identify pathways leading to T = 3, T = 4, and other experimentally observed capsid morphologies. The analysis shows that capsid polymorphism is promoted by the low HBV capsid bending modulus, where the key factors controlling polymorphism are the conformational energy landscape and protein-protein binding affinities.

Entropic force of cone-tethered polymers interacting with a planar surface.

Computer simulations are used to characterize the entropic force of one or more polymers tethered to the tip of a hard conical object that interact with a nearby hard flat surface. Pruned-enriched Rosenbluth method Monte Carlo simulations are used to calculate the variation of the conformational free energy F of a hard-sphere polymer with respect to the cone-tip-to-surface distance h from which the variation of the entropic force f≡|dF/dh| with h is determined. We consider the following cases: a single freely jointed tethered chain, a single semiflexible tethered chain, and several freely jointed chains of equal length each tethered to the cone tip. The simulation results are used to test the validity of a prediction by Maghrebi etal. [Maghrebi et al., Europhys. Lett. 96, 66002 (2011)0295-507510.1209/0295-5075/96/66002; Phys. Rev. E 86, 061801 (2012)1539-375510.1103/PhysRevE.86.061801] that f∝(γ_{∞}-γ_{0})h^{-1}, where γ_{0} and γ_{∞} are universal scaling exponents for the partition function of the tethered polymer for h=0 and h=∞, respectively. The measured functions f(h) are generally consistent with the predictions, with small quantitative discrepancies arising from the approximations employed in the theory. In the case of multiple tethered polymers, the entropic force per polymer is roughly constant, which is qualitatively inconsistent with the predictions.