Unconstrained Molecular Dynamics Simulations Research Articles

Kinetic reconstruction of free energies as a function of multiple order parameters.

A vast array of phenomena, ranging from chemical reactions to phase transformations, are analyzed in terms of a free energy surface defined with respect to a single or multiple order parameters. Enhanced sampling methods are typically used, especially in the presence of large free energy barriers, to estimate free energies using biasing protocols and sampling of transition paths. Kinetic reconstructions of free energy barriers of intermediate height have been performed, with respect to a single order parameter, employing the steady state properties of unconstrained simulation trajectories when barrier crossing is achievable with reasonable computational effort. Considering such cases, we describe a method to estimate free energy surfaces with respect to multiple order parameters from a steady state ensemble of trajectories. The approach applies to cases where the transition rates between pairs of order parameter values considered is not affected by the presence of an absorbing boundary, whereas the macroscopic fluxes and sampling probabilities are. We demonstrate the applicability of our prescription on different test cases of random walkers executing Brownian motion in order parameter space with an underlying (free) energy landscape and discuss strategies to improve numerical estimates of the fluxes and sampling. We next use this approach to reconstruct the free energy surface for supercooled liquid silicon with respect to the degree of crystallinity and density, from unconstrained molecular dynamics simulations, and obtain results quantitatively consistent with earlier results from umbrella sampling.

Predicted Adsorption Affinity for Enteric Microbial Metabolites to Metal and Carbon Nanomaterials.

Ingested nanomaterials are exposed to many metabolites that are produced, modified, or regulated by members of the enteric microbiota. The adsorption of these metabolites potentially affects the identity, fate, and biodistribution of nanomaterials passing the gastrointestinal tract. Here, we explore these interactions using in silico methods, focusing on a concise overview of 170 unique enteric microbial metabolites which we compiled from the literature. First, we construct quantitative structure–activity relationship (QSAR) models to predict their adsorption affinity to 13 metal nanomaterials, 5 carbon nanotubes, and 1 fullerene. The models could be applied to predict log k values for 60 metabolites and were particularly applicable to ‘phenolic, benzoyl and phenyl derivatives’, ‘tryptophan precursors and metabolites’, ‘short-chain fatty acids’, and ‘choline metabolites’. The correlations of these predictions to biological surface adsorption index descriptors indicated that hydrophobicity-driven interactions contribute most to the overall adsorption affinity, while hydrogen-bond interactions and polarity/polarizability-driven interactions differentiate the affinity to metal and carbon nanomaterials. Next, we use molecular dynamics (MD) simulations to obtain direct molecular information for a selection of vitamins that could not be assessed quantitatively using QSAR models. This showed how large and flexible metabolites can gain stability on the nanomaterial surface via conformational changes. Additionally, unconstrained MD simulations provided excellent support for the main interaction types identified by QSAR analysis. Combined, these results enable assessing the adsorption affinity for many enteric microbial metabolites quantitatively and support the qualitative assessment of an even larger set of complex and biologically relevant microbial metabolites to carbon and metal nanomaterials.

Thermodynamics and kinetics of crystallization in deeply supercooled Stillinger-Weber silicon.

We study the kinetics of crystallization in deeply supercooled liquid silicon employing computer simulations and the Stillinger-Weber three-body potential. The free energy barriers to crystallization are computed using umbrella sampling Monte Carlo simulations and from unconstrained molecular dynamics simulations using a mean first passage time formulation. We focus on state points that have been described in earlier work [S. Sastry and C. A. Angell, Nat. Mater. 2, 739 (2003)] as straddling a liquid-liquid phase transition (LLPT) between two metastable liquid states. It was argued subsequently [Ricci et al., Mol. Phys. 117, 3254 (2019)] that the apparent transition is due to the loss of metastability of the liquid state with respect to the crystalline state. The presence of a barrier to crystallization for these state points is therefore of importance to ascertain, which we investigate, with due attention to ambiguities that may arise from the choice of order parameters. We find a well-defined free energy barrier to crystallization and demonstrate that both umbrella sampling and mean first passage time methods yield results that agree quantitatively. Our results thus provide strong evidence against the possibility that the liquids at state points close to the reported LLPT exhibit slow, spontaneous crystallization, but they do not address the existence of a LLPT (or lack thereof). We also compute the free energy barriers to crystallization at other state points over a broad range of temperatures and pressures and discuss the effect of changes in the microscopic structure of the metastable liquid on the free energy barrier heights.

Hypervariability of accessible and inaccessible conformational space of proteins.

Proteins undergo motions in a range of amplitudes, from domain motions to backbone rotations, leading to changes in (φ,ψ) torsion angles and small-scale bond vibrations and angle bending. Here, we study the extent of variations in (φ,ψ) values in proteins and the effects of bond geometry variations due to vibrational motions in a protein on the accessible, (steric clash-free) (φ,ψ) space. We perform 1-fs timestep unconstrained molecular dynamics simulations on super-high-resolution protein structures. Extent of variations in bond geometry during the simulation is within acceptable ranges of bond lengths and angles. However, the steric clash-free (φ,ψ) space continuously changes as seen in bond geometry-specific (φ,ψ) steric maps at the residue level during simulations. (φ,ψ) regions that have steric clash at one timepoint can become steric clash-free at a different timepoint through minor adjustments to backbone bond lengths and angles. Also instances of (φ,ψ) transitions from the left to right half of the (φ,ψ) map in consecutive snapshots of the trajectory are seen. Although the two quadrants are separated by a steric clash-prone region, corresponding to a high-energy barrier, height of this barrier is lowered by adjusting the bond geometry such that a bridging region of steric clash-free, low-energy (φ,ψ) values is formed. We demonstrate the idea of dynamically varying nature of acceptable and accessible (φ,ψ) steric space in proteins, which has implications for protein folding; proteins could sample (φ,ψ) space which is originally considered to be inaccessible, during folding, through minor adjustments to their backbone bond geometry.

Molecular recognition of acetylcholinesterase and its subnanomolar reversible inhibitor: a molecular simulations study

Recently, we designed and synthesized a subnanomolar, reversible, dual-binding site acetylcholinesterase (AChE) inhibitor which consists of the tacrine and aroylacrylic acid phenylamide moieties, mutually linked by eight methylene units. To further investigate the process of the molecular recognition between the AChE and its inhibitor, we performed six unconstrained molecular dynamics (MD) simulations, where the compound in three possible protonation states was placed inside binding sites of two available AChE crystal structures. In all six MD trajectories, the ligand generally occupied similar space inside the AChE active site, but the pattern of the interactions between the ligand functional groups and the amino acid residues was significantly different and highly dependent upon the crystal structure used to generate initial systems for simulation. The greatest differences were observed between the trajectories obtained with different AChE crystal structures used as starting target conformations. In some trajectories, several unusual positions and dynamic behavior of the tacrine moiety were observed. Therefore, this study provides important structure-based data useful in further optimization of the reversible, dual binding AChE inhibitors, and also emphasizes the importance of the starting crystal structure used for dynamics as well as the protonation state of the reversible inhibitors. Communicated by Ramaswamy H. Sarma

Computational Modeling on Aquaporin-3 as Skin Cancer Target: A Virtual Screening Study.

Aquaporin-3 (AQP3) is one of the aquaglyceroporins, which is expressed in the basolateral layer of the skin membrane. Studies have reported that human skin squamous cell carcinoma overexpresses AQP3 and inhibition of its function may alleviate skin tumorigenesis. In the present study, we have applied a virtual screening method that encompasses filters for physicochemical properties and molecular docking to select potential hit compounds that bind to the Aquaporin-3 protein. Based on molecular docking results, the top 20 hit compounds were analyzed for stability in the binding pocket using unconstrained molecular dynamics simulations and further evaluated for binding free energy. Furthermore, examined the ligand-unbinding pathway of the inhibitor from its bound form to explore possible routes for inhibitor approach to the ligand-binding site. With a good docking score, stability in the binding pocket, and free energy of binding, these hit compounds can be developed as Aquaporin-3 inhibitors in the near future.

Molecular dynamics analysis of Mg2+ -dependent cleavage of a pistol ribozyme reveals a fail-safe secondary ion for catalysis.

Pistol ribozymes comprise a class of small, self-cleaving RNAs discovered via comparative genomic analysis. Prior work in the field has probed the kinetics of the cleavage reaction, as well as the influence of various metal ion cofactors that accelerate the process. In the current study, we performed unbiased and unconstrained molecular dynamics simulations from two current high-resolution pistol crystal structures, and we analyzed trajectory data within the context of the currently accepted ribozyme mechanistic framework. Root-mean-squared deviations, radial distribution functions, and distributions of nucleophilic angle-of-attack reveal insights into the potential roles of three magnesium ions with respect to catalysis and overall conformational stability of the molecule. A series of simulation trajectories containing in silico mutations reveal the relatively flexible and partially interchangeable roles of two particular magnesium ions within solvated hydrogen-bonding distances from the catalytic center.

Echo dephasing and heat capacity from constrained and unconstrained dynamics of triiodothyronine nuclear receptor protein.

The objective of this study is to observe the echo feature curves, vibrational dephasing, and heat capacity of a protein-hormone system taking thyroid hormone receptor-beta (THR-β) as an example. Constrained and unconstrained molecular dynamics simulations are performed by implementing the theory of velocity reassignments to probe the phase coherent state in terms of echo pulses. The constrained vibrations are incorporated by adjusting rigid bonds to all hydrogen atoms with an integrator parameter of 2fs/step in order to reduce the degrees of freedom whereas 1fs/step is used in the free vibrations of the atomic cluster. The nature of temperature auto-correlation functions changes so that echo feature curves also show a distinct nature in the cases of constrained and unconstrained vibrations. There is a large variation in kinetic temperature and internal potential energy in the echo time zone. The temperature rate of change of internal potential energy is the main contributor to the heat capacity of the native state protein-hormone system. The heat capacity of proteins estimated from this technique is in good agreement with the values from experiments. This study shows that triiodothyronine (T3) hormone makes some differences in heat capacity upon binding to the THR-β ligand binding domain (LBD). The physical properties of unliganded THR-β and T3-bound THR-β LBD in the cases of constrained and unconstrained dynamics are observed distinctly under the effect of anharmonicity on the phase coherent state of normal modes and the dephasing time lies in a range of 0.6-0.8ps when the systems are perturbed suddenly.

Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations.

We performed molecular dynamics (MD) simulations to obtain insights into the structure and molecular interactions of colloidal structures present in fasted state intestinal fluid. Drug partitioning and interaction were studied with a mixed system of the bile salt taurocholate (TCH) and 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLiPC). Spontaneous aggregation of TCH and DLiPC from unconstrained MD simulations at the united-atom level using the Berger/Gromos54A7 force fields demonstrated that intermolecular hydrogen bonding between TCH molecules was an important factor in determining the overall TCH and DLiPC configuration. In bilayered systems, these intermolecular hydrogen bonds resulted in embedded transmembrane TCH clusters. Free energy simulations using the umbrella sampling technique revealed that the stability of these transmembrane TCH clusters was superior when they consisted of 3 or 4 TCH per bilayer leaflet. All-atom simulations using the Slipids/GAFF force fields showed that the TCH embedded in the bilayer decreased the energy barrier to penetrate the bilayer (ΔGpen) for water, ethanol, and carbamazepine, but not for the more lipophilic felodipine and danazol. This suggests that diffusion of hydrophilic to moderately lipophilic molecules through the bilayer is facilitated by the embedded TCH molecules. However, the effect of embedded TCH on the overall lipid/water partitioning was significant for danazol, indicating that the incorporation of TCH plays a crucial role for the partitioning of lipophilic solutes into e.g. lipidic vesicles existing in fasted state intestinal fluids. To conclude, the MD simulations revealed important intermolecular interactions in lipidic bilayers, both between the bile components themselves and with the drug molecules.

Interaction of a calix[4]arene derivative with a DOPC bilayer: Biomolecular simulations towards chloride transport

The ability of a calix[4]arene derivative (CX-1), bearing four protonated NH3+ groups located in the upper rim and aliphatic tails in the lower rim, to interact with a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) model bilayer and promote transmembrane chloride transport was investigated by molecular dynamics (MD) simulations. Unconstrained MD simulations show that the interaction of CX-1 with DOPC occurs via the NH3+ groups, which are able to establish electrostatic interactions and multiple hydrogen bonds with the DOPC phosphate groups, while the aliphatic tails point towards the water phase (when CX-1 starts from the water phase) or to the membrane (when CX-1 is initially positioned within the bilayer). The interaction does not induce any relevant perturbation on the biophysical properties of the bilayer system (area per lipid, thickness, and hydration) apart from a systematic increase in the order parameter of the C2 carbon atom of the sn-1 lipid tail, meaning that the bilayer conserves its integrity. Since total internalization of CX-1 was not observed in the unconstrained MD time-scale, constant velocity steered molecular dynamics (SMD) simulations were performed in order to simulate the CX-1 permeation across the bilayer. At pulling velocities lower than 0.0075 nmps−1, chloride transport was observed. The Potential of Mean Force (PMF), calculated with the weighted histogram analysis method, indicates a barrier of ca. 58kJmol−1 for this mobile carrier to cross the membrane.

Nontrivial Behavior of Water in the Vicinity and Inside Lipid Bilayers As Probed by Molecular Dynamics Simulations

The atomic-scale diffusion of water in the presence of several lipid bilayers mimicking biomembranes is characterized via unconstrained molecular dynamics (MD) simulations. Although the overall water dynamics corresponds well to literature data, namely, the efficient braking near polar head groups of lipids, a number of interesting and biologically relevant details observed in this work have not been sufficiently discussed so far; for instance, the fact that waters "sense" the membrane unexpectedly early, before water density begins to decrease. In this "transitional zone" the velocity distributions of water and their H-bonding patterns deviate from those in the bulk solution. The boundaries of this zone are well preserved even despite the local (<1 nm size) perturbation of the lipid bilayer, thus indicating a decoupling of the surface and bulk dynamics of water. This is in excellent agreement with recent experimental data. Near the membrane surface, water movement becomes anisotropic, that is, solvent molecules preferentially move outward the bilayer. Deep in the membrane interior, the velocities can even exceed those in the bulk solvent and undergo large-scale fluctuations. The analysis of MD trajectories of individual waters in the middle part of the acyl chain region of lipids reveals a number of interesting rare phenomena, such as the fast (ca. 50 ps) breakthrough across the membrane or long-time (up to 750 ps) "roaming" between lipid leaflets. The analysis of these events was accomplished to delineate the mechanisms of spontaneous water permeation inside the hydrophobic membrane core. It was shown that such nontrivial dynamics of water in an "alien" environment is driven by the dynamic heterogeneities of the local bilayer structure and the formation of transient atomic-scale "defects" in it. The picture observed in lipid bilayers is drastically different from that in a primitive membrane mimic, a hydrated cyclohexane slab. The possible biological impact of such phenomena in equilibrated lipid bilayers is discussed.

Diffusion of 1,2-Dimethoxyethane and 1,2-Dimethoxypropane through Phosphatidycholine Bilayers: A Molecular Dynamics Study

In this paper, a theoretical study of 1,2-dimethoxyethane (DME) and 1,2-dimethoxypropane (DMP) at water/n-heptane and 1,2-dimyristoyl-sn-glycero-3-phospatidycholine (DMPC) lipid bilayer/water interfaces using the umbrella sampling method is reported. Recently proposed GROMOS96/OPLS compatible models for DME and DMP have been used for the simulation studies. The percolation free energy barrier of one DME and DMP molecule from water to n-heptane phase calculated using the umbrella sampling method turned out to be equal to ~18.5 kJ/mol and ~6 kJ/mol, respectively. In the case of the DMPC lipid bilayer, overall free energy barriers of ~20 kJ/mol and ∼12 kJ/mol were obtained for DME and DMP, respectively. The spontaneous diffusion of DME and DMP in the lipid bilayer has also been investigated using unconstrained molecular dynamics simulations at the water/DMPC interface and inside the lipid bilayer. As expected from the estimated percolation barriers, simulation results show that DME, contrary to DMP, spontaneously diffuse into the aqueous solution from the lipid interior. In addition, simulations with multiple DME or DMP molecules at the interface show spontaneous diffusion within 50 ns inside the DMPC layer only for DMP.

Towards an understanding of many-particle effects in hydrophobic association in methane solutions

This paper applies the multiscale coarse-graining method [S. Izvekov and G. A. Voth, J. Phys. Chem. B 109, 2469 (2005); J. Chem. Phys. 123, 134105 (2005)] to analyze many-body effects in concentrated methane solutions. Pairwise decompositions of N-particle solute-solute potentials of mean force (PMFs), and the respective solvent cavity potentials, enthalpic, entropic, and heat capacity of hydrophobic association, are calculated directly from unconstrained molecular-dynamics simulations of methane solutions at different molar fractions, with the highest being 0.055. The many-body effects in hydrophobic hydration are further studied using N-methane PMFs, which are explicitly dependent on solvent coordinates.

Evaluation of the binding ability of a macrobicyclic receptor for anions by potentiometry and molecular dynamics simulations in solution

Abstract The macrobicycle derived from bis-tren and containing diphenoxy groups as spacers, L1, was synthesized and used as receptor for anions. The binding ability of the new receptor for some aromatic carboxylates [phthalate (ph2−), isophthalate (iph2−), terephthalate (tph2−), benezenetricarboxylate (btc3−), and the herbicide 4-amino-3,5,6-trichloro-2-pyridinecarboxylate (ATCP−)], and the aliphatic cyclohexanetricarboxylate (ch3−) anions was evaluated by potentiometric measurements and molecular dynamic simulation in solution. The association constants were determined by potentiometry in H2O/MeOH (1:1 v/v) at 298.2 K and 0.10 mol dm−3 in KCl. The strongest association was found with btc3− anion and the effective binding constants at pH 5.5 follow the order: btc3−>tph2−>ph2−≈iph2−>ch3−≈ATCP−. Molecular dynamics simulations carried out for the associations of (H6L1)6+ with btc3−, tph2− and iph2− in the same mixture of solvents indicated that these anions interact with the receptor by a combination of electrostatic and multiple N–H⋯O C hydrogen bond interactions. It was also verified that in the recognition process the tph2− remained encapsulated over the entire time of simulation while the btc3− is partially inserted into the receptor cavity with one carboxylate group largely exposed to water solvent molecules, and iph2− anion exhibited an intermediate binding behaviour. The free energy difference between btc3− and iph2− associations estimated by free energy calculations is in excellent agreement with the difference found from the experimental values for the corresponding association constants, which indicates that the unconstrained molecular dynamics simulations carried out with these two anions are realistic pictures of their molecular recognition processes.

Molecular Dynamics Study of a Heteroditopic-Calix[4]diquinone-Assisted Transfer of KCl and Dopamine Through a Water−Chloroform Liquid−Liquid Interface

The ability of two heteroditopic calix[4]diquinone receptors to transport a KCl ion-pair and a dopamine zwitterion through a water-chloroform interface was investigated via molecular dynamics (MD) simulations. Gas-phase conformational analysis has been carried on KCl and dopamine receptor binding associations and the lowest energy structures found in both cases show that the recognition of KCl and dopamine zwitterion occurs through multiple and cooperative N-H...anion and O...cation bonding interactions, with the receptor adopting equivalent folded conformations stabilized by pi-stacking interactions. The unconstrained MD simulations performed on KCl and dopamine complexes inserted in either the chloroform or water phase revealed that receptors are preferentially located at the interface with the hydrophobic tert-butyl groups of the calix[4]diquinone moiety immersed in the chloroform bulk while the polar anion binding cavity is directed toward the water phase. When the KCl complex is placed in chloroform, the release of the ion-pair occurs only after the first contact with the water interface, being a nonsimultaneous event, with the chloride anion leaving the receptor before the potassium cation. The dopamine, via the -NH(3)(+) binding entity, remains bound to the receptor during the entire time of the MD simulation (10 ns). In contrast, when both complexes were inserted in the water bulk, the full release of KCl and dopamine are fast events. The potentials of mean force (PMFs), associated with the migration of the complexes from chloroform to water through the interface, were calculated from steered molecular dynamics (SMD) simulations. The PMFs for the free KCl and zwitterionic dopamine migrations were also obtained for comparison purposes. The transport of KCl from water to chloroform (the reverse path) mediated by the receptor has a free energy barrier estimated in 6.50 kcal mol(-1), which is 3.0 kcal mol(-1) smaller than that found for the free KCl. The transport of dopamine complex along the reverse path is characterized by downhill energy profile, with a small free energy barrier of 6.56 kcal mol(-1).

Lipid Membrane Composition has A Dramatic Effect on the Dynamics of the GlpG Rhomboid Protease from Escherichia Coli

Intramembrane proteases cleave transmembrane substrates to liberate physiologically important molecules. The proteolytic activity of these enzymes can be significantly influenced by the composition of the lipid membrane. Here, we find that the composition of the lipid membrane has a dramatic effect on the motions of the GlpG rhomboid serine protease from Escherichia coli.In a 1-palmytoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) lipid bilayer, conformational changes of two critical structural elements of the protease, the cap loop close to the active site and the regulatory loop L1, occur within 40ns of unconstrained molecular dynamics simulations. In contrast, in a 1-palmytoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE) lipid bilayer, a conformational transition of the cap loop is observed only after ∼80ns, ∼20ns after that of loop L1. This sensitivity of the enzyme motions on the lipid membrane composition is explained by differences in how POPC and POPE lipid headgroups hydrogen bond among themselves, and with protein amino acids. Tight interactions between a lipid headgroup and the active site restrict the dynamics of the cap loop.An atomistic description of the structure and dynamics of the protease:substrate complex is a critical first step towards understanding how the protease works. Molecular dynamics simulations of GlpG together with the Spitz model substrate reveal that docking of the substrate to the enzyme involves a complex interplay of changes in the structure and dynamics of the substrate, the protease, and the surrounding lipid molecules.This research was supported in part by the National Institute of General Medical Sciences (GM-74637 to S.H.W) and an allocation of computer time from the National Science Foundation through the TeraGrid resources at TACC (Ranger).

Can current force fields reproduce ring puckering in 2- O-sulfo-α- l-iduronic acid? A molecular dynamics simulation study

The monosaccharide 2- O-sulfo-α- l-iduronic acid (IdoA2S) is one of the major components of glycosaminoglycans. The ability of molecular mechanics force fields to reproduce ring-puckering conformational equilibrium is important for the successful prediction of the free energies of interaction of these carbohydrates with proteins. Here we report unconstrained molecular dynamics simulations of IdoA2S monosaccharide that were carried out to investigate the ability of commonly used force fields to reproduce its ring conformational flexibility in aqueous solution. In particular, the distribution of ring conformer populations of IdoA2S was determined. The GROMOS96 force field with the SPC/E water potential can predict successfully the dominant skew-boat to chair conformational transition of the IdoA2S monosaccharide in aqueous solution. On the other hand, the GLYCAM06 force field with the TIP3P water potential sampled transitional conformations between the boat and chair forms. Simulations using the GROMOS96 force field showed no pseudorotational equilibrium fluctuations and hence no inter-conversion between the boat and twist boat ring conformers. Calculations of theoretical proton NMR coupling constants showed that the GROMOS96 force field can predict the skew-boat to chair conformational ratio in good agreement with the experiment, whereas GLYCAM06 shows worse agreement. The omega rotamer distribution about the C5–C6 bond was predicted by both force fields to have torsions around 10°, 190°, and 360°.

Revisiting the planarity of nucleic acid bases: Pyramidilization at glycosidic nitrogen in purine bases is modulated by orientation of glycosidic torsion

We describe a novel, fundamental property of nucleobase structure, namely, pyramidilization at the N1/9 sites of purine and pyrimidine bases. Through a combined analyses of ultra-high-resolution X-ray structures of both oligonucleotides extracted from the Nucleic Acid Database and isolated nucleotides and nucleosides from the Cambridge Structural Database, together with a series of quantum chemical calculations, molecular dynamics (MD) simulations, and published solution nuclear magnetic resonance (NMR) data, we show that pyramidilization at the glycosidic nitrogen is an intrinsic property. This property is common to isolated nucleosides and nucleotides as well as oligonucleotides—it is also common to both RNA and DNA. Our analysis suggests that pyramidilization at N1/9 sites depends in a systematic way on the local structure of the nucleoside. Of note, the pyramidilization undergoes stereo-inversion upon reorientation of the glycosidic bond. The extent of the pyramidilization is further modulated by the conformation of the sugar ring. The observed pyramidilization is more pronounced for purine bases, while for pyrimidines it is negligible. We discuss how the assumption of nucleic acid base planarity can lead to systematic errors in determining the conformation of nucleotides from experimental data and from unconstrained MD simulations.

Molecular Dynamics Simulations Of Escherichia coli Acyl Carrier Protein Containing Fatty Acyl Derivatives

Acyl carrier protein (ACP) in bacteria and plants is an essential co-factor protein in fatty acid biosynthesis that shuttles covalently bound fatty acyl intermediates to various enzyme partners. Structures of apo-, holo-, and saturated acyl-ACPs indicate that the acyl groups are housed inside a hydrophobic binding cavity between three largely parallel helices. Molecular dynamics (MD) simulations have previously been used to illustrate the behaviour of various saturated acyl chains attached to ACP, in excellent agreement with experimental data. However, relatively little is known about the fatty acyl derivatives formed during the elongation of the acyl chains, namely the β-ketoacyl-, β-hydroxyacyl-, and enoyl-intermediates. ACP is one of the most abundant proteins in Escherichia coli and possesses a large number of interacting enzymes. As such, we seek to understand how the enzymes of fatty acid biosynthesis recognize which derivative is bound by ACP. To address this, we conducted numerous MD simulations of E. coli ACP with β-ketoacyl-, β-hydroxyacyl-, and enoyl- intermediates. The unconstrained MD simulations were set up with the attachment either in a solvent exposed or a solvent shielded conformation inside the hydrophobic binding pocket of ACP. We investigate a range of acyl group derivatives attached to ACP spanning from four to eighteen carbon groups in length to develop our understanding of the differences imparted on ACP by various acyl chain lengths. The results of the simulations of fatty acyl derivatives will provide a first look at the manner in which ACP accommodates these binding groups. What these data contribute to the understanding of enzyme:ACP interactions and substrate recognition by fatty acid synthase enzymes will be discussed.

A Molecular Dynamics Study on the Binding and Interaction of the Amyloid-Beta (1-42) Peptide with Phospholipid Bilayers

The Amyloid-Beta (A-Beta) peptide is a key aggregate species in Alzheimer's disease. While aspects of the A-Beta peptide aggregation pathway have previously been elucidated, the initial conversion of monomer peptides into an oligomer during aggregation is not clearly understood. One potential mediator of these early stages of aggregation is interactions of A-Beta with cell membranes, particularly anionic cell membranes. We use unconstrained and umbrella sampling molecular dynamics simulations to investigate interactions between the 42-amino acid A-Beta peptide and model bilayers consisting of zwitterionic dipalmitoylphophatidylcholine (DPPC) lipids and anionic dioleoylphosphatidylserine (DOPS) lipids. From this work, we determine that A-Beta binds to the surface of DPPC and DOPS bilayers over the small length scales used in simulations. Our results also support the hypothesis that the charge on the bilayer surface and on the peptide affects both the free energy of peptide-membrane binding and the distribution of the peptide on the bilayer surface. Finally, no significant secondary structure change is observed in the peptide during the timescales used in these simulations. This result may indicate all-atom simulation times are too short to observe secondary structure changes in this system or that structure change during the oligomerization process requires peptide-peptide interactions. Our work demonstrates that interactions between the A-Beta peptide and lipid bilayers promote a peptide distribution on the bilayer surface that is prone to peptide-peptide interactions, which can influence the propensity of A-Beta to aggregate into higher order structures.