Dynamics Simulations Of Aqueous Solutions Research Articles

Counter-ion adsorption and electrostatic potential in sodium and choline dodecyl sulfate micelles - a molecular dynamics simulation study.

Choline-based surfactants are interesting both from the practical point of view to obtaining environmental-friendly surfactants as well as from the theoretical side since the interactions between the choline and surfactants can help to understand self-assembly phenomena in deep eutectic solvents. Although no significant change was noticed in the micelle size and shape due to the exchange of the sodium counter-ion by choline in our simulations, the adsorption of the choline cation over the micelle surface is stronger than the adsorption of the sodium, which leads to a reduction of the exposed surface area of the micelle and remarkable effects over the electrostatic potential. The choline neutralizes the surface charge of the surfactant better than sodium; however, this is partially compensated by a stronger water orientation around the SDS micelle. The balance between the contributions from the surfactant, the counter-ion, and water to the electrostatic potential leads to a complex pattern with alternate regions of positive and negative potential at the micelle/water interface which can be important to the incorporation of other charged species at the micelle surface as well as for the interaction between micelles in solution. To evaluate the effects of the counter-ion substitution, micelles of sodium dodecyl sulfate (SDS) and choline dodecyl sulfate (ChDS) were studied and compared by means of molecular dynamics simulations in aqueous solution. In both cases, the simulations started from pre-assembled micelles with 60 dodecyl sulfate ions and 240-ns simulations were performed at NPT ensemble at T = 323.15K and P = 1bar using the Gromacs software with the OPLS-AA force field to describe dodecyl sulfate and choline, Åqvist parameters for sodium, and SPC model for water molecules.

Computational investigation of conformational fluctuations of Aβ42 monomers in aqueous ionic liquid mixtures

Aggregation of intrinsically disordered proteins (IDPs) is often triggered by protein–protein interaction, leading to several neurodegenerative diseases.In this study, we aim to understand the role of 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4] ionic liquid (IL) on altering secondary structure of the peptide and study the interactions responsible for their conformational modification. Here we report structural features of an ensemble of amyloid beta (Aβ42) peptide monomers employing all-atom molecular dynamics simulations in aqueous solution of IL at room temperature. Our calculations reveal, Aβ42 peptide exhibit rapidly inter-converting conformations adopting extended chain as well as collapsed coil-like structures with a propensity to form few transient α-helices and β-sheets at intermediate times. We have correlated this higher flexibility of the peptide with formation of less stable salt-bridge in presence of IL in aqueous solution. It is found that water molecules around the polar regions are more structured imparting structural rigidity to the peptide backbone than around the hydrophobic domains. Thus identifying the effect of electrostatic interaction of IL on expulsion of water molecules from the polar domains on the peptide surface can shed light on preventing the aggregation process. We have also determined the most energetically stable peptide conformations from various accessible intermediate states using metadynamics simulations that are characterized by the rugged free energy surface having multiple energy basins.

Ion Size Dependences of the Salting-Out Effect: Reversed Order of Sodium and Lithium Ions.

A general trend of the salting-out effect on hydrophobic solutes in aqueous solution is that the smaller the size of a dissolved ion, the larger the effect of reducing the solubility of a hydrophobe. An exception is that Li+, the smallest in alkali metal ions, has a notably weaker effect than Na+. To understand the reversed order in the cation series, we performed molecular dynamics simulations of aqueous solutions of salt ions and calculated the Setschenow coefficient of methane with the ionic radius of either a cation or an anion varied in a wide range. It is confirmed that the Setschenow coefficient is correlated with the packing fraction of salt solution, as observed in earlier studies, and also correlated with the partial molar volume of an ion. Analyses of correlation function integrals, packing fractions of solvation spheres, and orientations of water molecules surrounding an ion reveal the key differences in microscopic properties between the cation and anion series, which give rise to the reversed order in the cation series of the partial molar volumes of ions and ultimately that of the Setschenow coefficients.

Lorentz forces induced by a static magnetic field have negligible effects on results from classical molecular dynamics simulations of aqueous solutions

A static external magnetic field is included in molecular dynamics simulations of aqueous solutions, and the effects on static and dynamic properties are determined. It is pointed out that diamagnetic properties are generally negligible if small molecules or ions are considered. Therefore, particular attention is paid to the effects arising from the Lorentz force acting on the (partial) charges on water, atomic ions, and larger molecules in solution. Careful analysis of many macroscopic and microscopic properties is performed for systems in magnetic fields of up to 1 T. None of the properties is found to be significantly affected by the Lorentz force. It is shown that any apparent variations with magnetic-field strength are simply statistical fluctuations. It is emphasized that the magnitude of the Lorentz force is up to eight orders of magnitude smaller than the average force coming from nonmagnetic forces and thermal fluctuations in the liquid phase at normal temperatures. The results are complemented by a theoretical argument which precludes Lorentz-force effects. A discussion of earlier reports of significant magnetic-field effects is presented.

Molecular dynamics simulations of aqueous solutions of short chain alcohols. Excess properties and the temperature of maximum density

The excess enthalpy hE and excess volume vE of the binary systems {methanol, ethanol, 1-propanol, 2-propanol, and tert-butanol + water} over the whole composition range at 298.15 K and the temperature of maximum density, TMD, in the alcohol diluted region were studied by MD simulations at atmospheric pressure. Our model systems were defined using the flexible version of the TIP4P/2005 model of water, the OPLS-AA for alcohols, and the geometric combining rule for all the Lennard-Jones cross interactions, with the exception of those between oxygen sites of water and alcohol molecules. These latter values were fitted to reproduce the experimental excess properties of the mixtures. This new parameterization allows for an appropriate description of the excess thermodynamics of these short-chain alcohol/water systems over the whole composition range. The changes in the temperature of maximum density of water induced by the addition of small amounts of alcohol concentration are, however, not adequately reproduced by our models. In all instances we observe a pronounced decrease of the simulated TMDs when alcohol concentration increases. This is in sharp contrast with the experimental behavior, which at very high dilution displays slight increases in the TMD right before the decreasing regime sets in for higher alcohol concentrations. For similar alcohol mole fractions, the simulated decrease of the TMDs grows in parallel with the size of the alkyl group of the alcohol. A similar situation is found experimentally for concentrations higher than those that increase the TMD. These differences disappear when the TMD change is expressed in terms of the mass concentration of alcohol. This leads to very similar Despretz constants for all solutions studied in this work.

Stilbene-based natural compounds as promising drug candidates against COVID-19

The pandemic coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a great threat to public health. Currently, no potent medicine is available to treat COVID-19. Quest for new drugs especially from natural plant sources is an area of immense potential. The current study aimed to repurpose stilbenoid analogs, reported for some other biological activities, against SARS-CoV-2 spike protein and human ACE2 receptor complex for their affinity and stability using molecular dynamics simulation and binding free energy analysis based on molecular docking. Four compounds in total were probed for their binding affinity using molecular docking. All of the compounds showed good affinity (> −7 kcal/mol). However, fifty nanoseconds molecular dynamic simulation in aqueous solution revealed highly stable bound conformation of resveratrol to the viral protein: ACE2 receptor complex. Net free energy of binding using MM-PBSA also affirmed the stability of the resveratrol-protein complex. Based on the results, we report that stilbene based compounds in general and resveratrol, in particular, can be promising anti-COVID-19 drug candidates acting through disruption of the spike protein. Our findings in this study are promising and call for further in vitro and in vivo testing of stiblenoids, especially resveratrol against the COVID-19. Communicated by Ramaswamy H. SarmaHighlightsStilbenoid analogs could be potential disruptors of SARS-CoV-2 spike protein and human ACE2 receptor complex.In particular, resveratrol revealed highly stable conformation to the viral protein: ACE2 receptor complex.The strong interaction of resveratrol is affirmed by molecular dynamic simulation studies and better net free energies.

Dynamical Model for the Counteracting Effects of Trimethylamine N-Oxide on Urea in Aqueous Solutions under Pressure.

Of cosolutes found in living cells, urea denatures and trimethylamine N-oxide (TMAO) stabilizes proteins; furthermore, these effects cancel at a 2:1 ratio of urea to TMAO. Interestingly, cartilaginous fish use urea and TMAO as osmolytes at similar ratios at the ocean surface but with increasing fractions of TMAO at increasing depths. Here, molecular dynamics simulations of aqueous solutions with different urea:TMAO ratios show that the diffusion coefficients of water in the solutions vary with pressure if the urea:TMAO ratio is constant, but strikingly, they are almost pressure independent at the ratio found in these fish as a function of depth. This suggests that this ratio may be maintaining a homeostasis of water dynamics. In addition, diffusion is determined by hydrogen-bond lifetimes of the different species in the solution. Based on these observations, a dynamical model in terms of hydrogen-bond lifetimes is developed for the hydrogen bonding propensities of cosolutes and water in an aqueous solution to proteins. This model provides an explanation for both the counteracting effects of TMAO on urea denaturation and the depth-dependent urea:TMAO ratio found in cartilaginous fish.

Aggregation Patterns in Low- and High-Charge Anions Define Opposite Solubility Trends.

Molecular dynamics simulations in aqueous solution reveal the existence of two distinct patterns of aggregation in low and high charge density Lindqvist-type polyoxometalates (POMs). Our results indicate the presence of contact and solvent-shared ion pairs and specific and preferential interactions of alkalis with POMs. Highly charged POMs are capable of breaking apart the Li+ and Cs+ solvation shell, thus enhancing the formation of long-lived alkali-POM contact ion pairs, where alkalis act as an electrostatic "glue" forming large oligomers. Stronger ion pair interactions for Li+ than for Cs+ promote lower solubility for Li+ than for Cs+, evoking anomalous solubility trends. Lower charge density POMs are not capable of disrupting the Li+ solvation shell and only solvent-shared ion pairs are formed, whereas for Cs+, contact ion pairs exist. The large number of oxygen atoms in the POM surface enhances the hydrogen bonds between POM and water, thus promoting aggregation. In this case, aggregation follows normal solubility trends. Thus, aggregation depends on the strength of ion pair interactions, the capacity of POM to disrupt alkali's solvation shell, and the contact surface area between the solvent and POM.

Blocking the catalytic mechanism of MurC ligase enzyme from Acinetobacter baumannii: An in Silico guided study towards the discovery of natural antibiotics

Acinetobacter baumannii belongs to the most critical group of bacterial pathogens that are resistant to large number of antibiotics, including the highly effective carbapenems and third generation cephalosporins. Novel antibiotics targeting unique pathways of the said pathogen could reduce the mortality rate due to its infections that are impervious to the current antibiotics. Herein, we explored a library of natural compounds that was filtered first for drug-like, followed by lead-like molecules, which were finally utilized in structure based virtual screening to identify the most promising inhibitor for the Ligand binding (LB) domain of MurC ligase enzyme. The inhibitor (1′-((2H-imidazol-2-yl)methyl)-N-(pyridin-2-yl)-1′,2′-dihydro-[4,4′-bipyridin]-2-amine) was observed with a conformation to target most conserved and catalytically critical residues of both the intended LB as well as the ATP binding domain of MurC. This multi-domain inhibitor revealed to have an excellent pharmacokinetics profile thus likely to have safe and effective therapeutic applications for the future. Molecular dynamics simulation in aqueous solution further supported the high affinity of the compound for the target site involving strong hydrogen bonding. At residue level, radial distribution function (RDF) and axial distribution function (AFD) illustrated Asp334 as the most critical amino acid that drives recognition, binding, and activity of the compound. The complex stability was validated by subjecting it to Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA), Molecular Mechanics Generalized Born Surface Area (MMGBSA) and WaterSwap based binding free energy calculations. The system was observed with high stability: total binding energy in MMGBSA (−48.45 kcal/mol) and MMPBSA (−3.62 kcal/mol). The columbic interactions were noticed to dominate (−336.90 kcal/mol), followed by van der Waals energies (−45.52 kcal/mol) in MurC-inhibitor binding. The absolute binding free energy estimated by WaterSwap was −43.2 kcal/mol, depicting higher complex stability. The screened scaffold might be used in functional groups substitution to achieve further lead optimization.

Molecular Dynamics Simulations of Furfural and 5-Hydroxymethylfurfural at Ambient and Hydrothermal Conditions.

In this work, we present results from molecular dynamics simulations of aqueous solutions of furfural and 5-hydroxymethylfurfural, which are important intermediates in the hydrothermal carbonization processes of biomass conversion. The computations were performed both at ambient and hydrothermal conditions using a two-level factorial design varying concentration, temperature, and pressure. A number of equilibrium and dynamic properties have been computed including enthalpies and free energies of vaporization, free energies of solvation, diffusion coefficients, and rotational/reorientational correlation times. Structural properties of solutions were analyzed using radial and spatial distribution functions. It was shown that the formation of hydrogen bonds among 5-hydroxymethylfurfural molecules is preferred compared to hydrogen bonding between 5-hydroxymethylfurfural and water. In addition, our results suggest that the oxygen atoms in the furan rings of furfural and 5-hydroxymethylfurfural do not participate in hydrogen bonding to the same extent as the oxygen atoms in the hydroxyl and carbonyl groups. It is also observed that furfural molecules aggregate under certain conditions, and we show how this is affected by changes in temperature, pressure, and concentration in agreement with experimental solubility data. The analysis of the computational results provides useful insight into the structure and dynamics of the considered molecules at conditions of hydrothermal carbonization, as well as at ambient conditions.

Temperature effect on the structure and conformational fluctuations in two zinc knuckles from the mouse mammary tumor virus

Zinc fingers are small protein domains in which zinc plays a structural role, contributing to the stability of the zinc–peptide complex. Zinc fingers are structurally diverse and are present in proteins that perform a broad range of functions in various cellular processes, such as replication and repair, transcription and translation, metabolism and signaling, cell proliferation, and apoptosis. Zinc fingers typically function as interaction modules and bind to a wide variety of compounds, such as nucleic acids, proteins, and small molecules. In this study, we investigated the structural properties, in solution, of the proximal and distal zinc knuckles of the nucleocapsid (NC) protein from the mouse mammary tumor virus (MMTV) (MMTV NC). For this purpose, we performed a series of molecular dynamics simulations in aqueous solution at 300 K, 333 K, and 348 K. The temperature effect was evaluated in terms of root mean square deviation of the backbone atoms and root mean square fluctuation of the coordinating residue atoms. The stability of the zinc coordination sphere was analyzed based upon the time profile of the interatomic distances between the zinc ions and the chelator atoms. The results indicate that the hydrophobic character of the proximal zinc finger is dominant at 333 K. The low mobility of the coordinating residues suggests that the strong electrostatic effect exerted by the zinc ion on its coordinating residues is not influenced by the increase in temperature. The evolution of the structural parameters of the coordination sphere of the distal zinc finger at 300 K gives us a reasonable picture of the unfolding pathway, as proposed by Bombarda and coworkers (Bombarda et al., 2005), which can predict the binding order of the four conserved ligand-binding residues. Our results support the conclusion that the structural features can vary significantly between the two zinc knuckles of MMTV NC.

Molecular Dynamics Study of the Solution Structure, Clustering, and Diffusion of Four Aqueous Alkanolamines.

CO2 sequestration from anthropogenic resources is a challenge to the design of environmental processes at a large scale. Reversible chemical absorption by amine-based solvents is one of the most efficient methods of CO2 removal. Molecular simulation techniques are very useful tools to investigate CO2 binding by aqueous alkanolamine molecules for further technological application. In the present work, we have performed detailed atomistic molecular dynamics simulations of aqueous solutions of three prototype amines: monoethanolamine (MEA) as a standard, 3-aminopropanol (MPA), 2-methylaminoethanol (MMEA), and 4-diethylamino-2-butanol (DEAB) as potential novel CO2 absorptive solvents. Solvent densities, radial distribution functions, cluster size distributions, hydrogen-bonding statistics, and diffusion coefficients for a full range of mixture compositions have been obtained. The solvent densities and diffusion coefficients from simulations are in good agreement with those in the experiment. In aqueous solution, MEA, MPA, and MMEA molecules prefer to be fully solvated by water molecules, whereas DEAB molecules tend to self-aggregate. In a range from 30/70-50/50 (w/w) alkanolamine/water mixtures, they form a bicontinuous phase (both alkanolamine and water are organized in two mutually percolating clusters). Among the studied aqueous alkanolamine solutions, the diffusion coefficients decrease in the following order MEA > MPA = MMEA > DEAB. With an increase of water content, the diffusion coefficients increase for all studied alkanolamines. The presented results are a first step for process-scale simulation and provide important qualitative and quantitative information for the design and engineering of efficient new CO2 removal processes.

Solvation of Methyl Lactate in Water: Molecular Dynamics Studies.

Methyl lactate (ML), a chiral α-hydroxy ester, has been probed widely to understand the competition between two types of intramolecular H-bonds in solvents of different polarities. Recent experimental and high-level quantum chemical studies have revealed the predominant existence of ML-water insertion complexes over addition complexes in aqueous solution. Although the stability of monohydrate insertion conformer was studied accurately, ab initio quantum chemical calculations failed to predict the most stable dihydrate conformer in analogy with the experimental spectroscopic search. Atomistic molecular dynamics simulations of aqueous solution of methyl lactate predict that the population and lifetime of different H-bonded ML-water addition complexes are dictated by their interaction energies. Although the population of dihydrate insertion complexes is higher than that of the monohydrate complexes, the lifetime of the former is smaller than the latter, which is in good agreement with the experimental result. The nature of intramolecular H-bonds within a methyl lactate molecule in aqueous solution is opposite to that in the gas phase due to the solvation process in water by intermolecular H-bonding interactions.

Characterization of the interaction forces in a drug carrier complex of doxorubicin with a drug-binding peptide.

Polypeptide-based materials are used as building blocks for drug delivery systems aimed at toxicity decrease in chemotherapeutics. A molecular-level approach is adopted for investigating the non-covalent interactions between doxorubicin and a recently synthesized drug-binging peptide as a key part of a system for delivery to neoplastic cells. Molecular dynamics simulations in aqueous solution at room and body temperature are applied to investigate the structure and the binding modes within the drug-peptide complex. The tryptophans are outlined as the main chemotherapeutic adsorption sites, and the importance of their placement in the peptide sequence is highlighted. The drug-peptide binging energy is evaluated by density functional theory calculations. Principal component analysis reveals comparable importance of several types of interaction for the binding strength. π-Stacking is dominant, but other factors are also significant: intercalation, peptide backbone stacking, electrostatics, dispersion, and solvation. Intra- and intermolecular H-bonding also stabilizes the complexes. The influence of solvent molecules on the binding energy is mild. The obtained data characterize the drug-to-peptide attachment as a mainly attractive collective process with interactions spanning a broad range of values. These results explain with atomistic detail the experimentally registered doxorubicin-binging ability of the peptide and outline the complex as a prospective carrying unit that can be employed in design of drug delivery systems.

Photoisomers of Azobenzene Star with a Flat Core: Theoretical Insights into Multiple States from DFT and MD Perspective.

This study focuses on comparing physical properties of photoisomers of an azobenzene star with benzene-1,3,5-tricarboxamide core. Three azobenzene arms of the molecule undergo a reversible trans-cis isomerization upon UV-vis light illumination giving rise to multiple states from the planar all-trans one, via two mixed states to the kinked all-cis isomer. Employing density functional theory, we characterize the structural and photophysical properties of each state indicating a role the planar core plays in the coupling between azobenzene chromophores. To characterize the light-triggered switching of solvophilicity/solvophobicity of the star, the difference in solvation free energy is calculated for the transfer of an azobenzene star from its gas phase to implicit or explicit solvents. For the latter case, classical all-atom molecular dynamics simulations of aqueous solutions of azobenzene star are performed employing the polymer consistent force field to shed light on the thermodynamics of explicit hydration as a function of the isomerization state and on the structuring of water around the star. From the analysis of two contributions to the free energy of hydration, the nonpolar van der Waals and the electrostatic terms, it is concluded that isomerization specificity largely determines the polarity of the molecule and the solute-solvent electrostatic interactions. This convertible hydrophilicity/hydrophobicity together with readjustable occupied volume and the surface area accessible to water, affects the self-assembly/disassembly of the azobenzene star with a flat core triggered by light.

Phase behavior of aqueous polyacrylic acid solutions using atomistic molecular dynamics simulations of model oligomers

We have performed fully atomistic molecular dynamics simulations of aqueous solutions of a weak, pH-responsive polyelectrolyte, polyacrylic acid (PAA). Model oligomers of PAA of different tacticities, molecular weights, degrees of deprotonation, and deprotonation patterns are simulated with water molecules. Deprotonation of PAA chains that occurs with an increase in pH results in an increase in Coulomb repulsion between chain segments on one hand, and a non-monotonic change in the hydrogen bonding between chain segments on the other hand. Consequently, at the single chain level, PAA chains are stretched at higher pH values, where the amount of stretching varies with chain tacticity. For the multiple chains case, PAA forms aggregates at higher concentrations, which are relatively denser and contain lesser water (solid-like) at lower pH than compared to higher pH (liquid-like). Such phase transitions of PAA aggregates with pH has possible implications in the design of pH-responsive polyelectrolytes for applications in drug delivery.

Stability of a Split Streptomycin Binding Aptamer.

Here we investigated the stability of an aptamer, which is formed by two RNA strands and binds the antibiotic streptomycin. Molecular dynamics simulations in aqueous solution confirmed the geometry and the pattern of hydrogen bond interactions that was derived from the crystal structure (1NTB). The result of umbrella sampling simulations indicated a favored streptomycin binding with a free energy of ΔGbind° = −101.7 kJ mol–1. Experimentally, the increase in oligonucleotide stability upon binding of streptomycin was probed by single-molecule force spectroscopy. Rate dependent force spectroscopy measurements revealed a decrease in the natural off-rate (koff-COMPLEX = 0.22 ± 0.16 s–1) for the aptamer–streptomycin complex compared to the aptamer having an empty binding pocket (koff-APTAMER = 0.49 ± 0.11 s–1). This decrease in the natural off-rate corresponds to a decrease in the Gibbs free energy of ΔΔGsheer ≈ −3.4 kJ mol–1. The simulated binding pattern and the experimental results led to the conclusion that...

Molecular dynamics simulation of a DNA duplex labeled with triarylmethyl spin radicals

All-atom molecular dynamics simulation of aqueous solution of DNA duplex with triarylmethyl (TAM) spin labels attached to its ends through piperazine linkers has been carried out. The dynamics and structure of the resulting molecule on time scales up to 2μs has been studied. Two classes of specific conformations have been observed. In the first one, a duplex retains its structure, and the labels on the average are arranged above the end bases of the duplex. Another class is related to the appearance of fraying at the duplex ends, i.e. involves situations where bonds between the end bases are broken, and the end pair is open. In this case, the labels get additional opportunities for the movement. Furthermore, due to torsional rotations in the linker, large deviations from the equilibrium states are possible. It is discussed the detected fraying of duplex labeled with TAM is not the inevitable result of the impact of labels. Our additional simulation has shown that fraying also occurs in the duplex without labels. Thus, despite its size, the TAM spin label does not critically influence the structure of the duplex. The distribution of distance between the labels for conformations of duplex without fraying has been shown to be in good agreement with the experimental distribution measured by pulsed EPR for the same molecule immobilized on a substrate in an aqueous solution.

Proton transfer from water to anion: Free energy profile from first principles metadynamics simulations

We elucidate the characteristic proton transfer process from water to aniline anion, and the free energy profile of the process in aqueous solution from the first principles simulations. We have explored the structure and energetic of hydrated clusters of aniline anion with up to three water molecules by gas phase electronic structure calculations. Our results indicate that the proton transfer in hydrated clusters proceeds more easily as the number of water molecule increases. The presence of minimum three water molecules in the gas phase cluster is sufficient to facilitate the proton transfer process from water to anion. The analysis of trajectories obtained from density functional theory based first principles molecular dynamics simulations of aqueous solution of anion do not show any evident of complete transfer of proton from water to anion due to energy barrier, and cooperativity of other surrounding water molecules. Using biasing potential through first principles metadynamics simulations, we report the observation of proton transfer reaction from water to aniline anion with a barrier height of 27.7kJ/mol. In the aqueous solution of the anion, and beyond the critical number of solvent water molecules in hydrated clusters, one of the adjacent water molecules becomes more acidic and gives its proton to anion. Our observations are in agreement with the observation from experimental study.

Conformations of Low-Molecular-Weight Lignin Polymers in Water.

Low-molecular-weight lignin binds to cellulose during the thermochemical pretreatment of biomass for biofuel production, which prevents the efficient hydrolysis of the cellulose to sugars. The binding properties of lignin are influenced strongly by the conformations it adopts. Here, we use molecular dynamics simulations in aqueous solution to investigate the dependence of the shape of lignin polymers on chain length and temperature. Lignin is found to adopt collapsed conformations in water at 300 and 500 K. However, at 300 K, a discontinuous transition is found in the shape of the polymer as a function of the chain length. Below a critical degree of polymerization, Nc =15, the polymer adopts less spherical conformations than above Nc. The transition disappears at high temperatures (500 K) at which only spherical shapes are adopted. An implication relevant to cellulosic biofuel production is that lignin will self-aggregate even at high pretreatment temperatures.