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PubMed1997

Calculation of Protein-Polymer Force Fields Using Molecular Dynamics

Molecular dynamics simulations were performed to determine the force field of attraction between Leu-enkephalin and a model polyethylene surface. Four separate rotational orientations of the polypeptide were simulated. During the simulations the surface atoms were held static, but the water atoms were dynamic. Some simulations were studied employing restricted dynamics of the polypeptide in which only the five backbone alpha-carbon atoms held immobile. For an orientation with oxygen atoms toward the PE surface the force between the enkephalin and the surface was repulsive and was approaching zero as the separation reached 8 A. The maximum repulsive force reached 8 kcal/mole/A at 2.7 A separation. For an orientation with hydrophobic groups toward the PE, the force was attractive with a minimum in the force field of 4 kcal/mole/A at 2.3 A. Two other orientations were also investigated. The results of the MD simulations indicated that the force between enkephalin and PE in the region 0 < z < 9.5 A was mostly a function of the separation distance and the orientation angle of enkephalin with respect to the surface.

Journal Article↗
PubMed2007

Effect of cluster size in kiloelectronvolt cluster bombardment of solid benzene.

Emission of benzene molecules by 5-keV cluster bombardment of a range of carbon projectiles from C6H6 to C180 is studied by a coarse-grained molecular dynamics (MD) technique. This approach permits calculations that are not feasible using more complicated potential energy functions, particularly as the interesting physics associated with the ion impact event approaches the mesoscale. These calculations show that the highest ejection yields are associated with clusters that deposit their incident energy 15-20 A below the surface. The highest yield for the projectiles is produced by the C20 and C60 projectiles. The results from the MD simulations are also compared favorably to an analytical model based on fluid dynamics to describe the energy deposition. The analytical model is then utilized to extend the range of the calculations to higher incident energies. The issue of the relative amount of chemical fragmentation and intact molecular desorption is also examined for the benzene crystal. These results show that damage accumulation at high-incident fluence should not be problematic and that it should be possible to perform molecular depth profiling via secondary ion mass spectrometry experiments. In general, the approach presented here illustrates the power of combining a simplified MD method with analytical strategies for describing a length scale that is difficult to achieve with traditional MD calculations.

Benzene↗
PubMed2004

Molecular simulation studies of a selenium-containing scFv catalytic antibody that mimics glutathione peroxidase.

GPX is a mammalian antioxidant selenoenzyme which protects biomembranes and other cellular components from oxidative damage by catalyzing the reduction of a variety of hydroperoxides (ROOH), using Glutathione (GSH) as the reducing substrate. The single-chain Fv fragment of the monoclonal antibody 2F3 (scFv2F3) can be converted into the selenium-containing Se-scFv2F3 by chemical modification of the serine. The new selenium-containing catalytic antibody Se-scFv2F3 acts as a glutathione peroxidase (GPX) mimic with high catalytic efficiency. In order to investigate which residue of scFv2F3 is converted into selenocysteine and to describe the proper reaction site of GSH to Se-scFv2F3, a three-dimensional structure of scFv2F3 is built by means of homology modeling. The 3D model is assessed by molecular dynamics (MD) simulation to determine its stability and by comparison with those of known protein structures. After the serine in the scFv2F3 is modified to selenocysteine, a catalytic antibody (abzyme) is obtained. From geometrical considerations, the solvent-accessible surface of the protein is examined. The computer-aided docking and energy minimization (EM) calculations of the abzyme-GSH complex are then carried out to explore the possible active site of the glutathione peroxidase mimic Se-scFv2F3. The structural information from the theoretically modeled complex can help us to further understand the catalytic mechanism of GPX.

Amino Acid Sequence↗
PubMed2026

Computational discovery of emodin-based anthraquinones as PARP-1 inhibitors with relevance to ovarian and prostate cancer.

Cancer is a disease characterized by genomic instability and aberrant DNA repair. Poly (ADP-ribose) polymerase-1 (PARP-1) represents a well-established therapeutic target, particularly in ovarian and prostate cancer. However, the currently approved PARP inhibitors face challenges such as resistance, toxicity, and reduced efficacy. The search for alternative scaffolds has therefore become increasingly urgent. In this study, we used an integrated approach combining computer-aided methods to search for potential lead compounds among emodin-based anthraquinone derivatives as PARP-1 inhibitors. Using a PASS-based QSAR approach, drug-likeness prediction, and in silico ADMET assessment, we pre-screened a large set of anthraquinones and identified several potential hits for interaction with PARP-1. These hits were studied using molecular docking with the PARP-1 catalytic domain (PDB ID: 7KK4). The most stable and compact complexes were further explored by 500&#xa0;ns molecular dynamics (MD) simulations and various dynamic properties (RMSD, RMSF, Rg, SASA, MolSA, hydrogen bonds, PCA, DCCM). The key finding of this study is that several emodin-derived anthraquinones exhibited binding behavior and ADMET profiles comparable to, or better than, the reference PARP-1 inhibitor. Among them, CID-10425624 emerged as the most promising candidate, exhibiting stable binding, reduced conformational fluctuation, compact complex formation, persistent hydrogen-bond interactions, and enhanced dynamic residue correlations within the PARP-1 catalytic domain. These findings suggest that the anthraquinone scaffold can provide a valuable starting point for developing structurally distinct PARP-1 inhibitors. In summary, this study identified several emodin-derived anthraquinones, particularly CID-10425624, as computationally prioritized lead candidates for PARP-1 inhibition, providing a novel anthraquinone-based scaffold for further experimental validation and optimization.

Anthraquinones↗
PubMed2006

Molecular dynamics simulation and automated docking of the pro-apoptotic Bax protein and its complex with a peptide designed from the Bax-binding domain of anti-apoptotic Ku70.

Bax, a multi-domain protein belonging to the large family of Bcl-2 proteins, has a pivotal role for the initiation of the cytochrome c-mediated apoptosis, a vital physiologic process to eliminate damaged or unwanted cells. In response to specific stimuli Bax translocates from cytosol to mitochondria outer membrane where a process of oligomerization occurs with pore formation through which cytochrome c and other death molecules escape. The pro-death action of Bax is regulated by the interaction with other pro-survival proteins. However, the conformational changes and the structural details necessary for homo and hetero interaction with other regulating proteins are largely unknown. This article reports a combined investigation of molecular dynamics (MD) simulation and automated docking that evidence the molecular regions of Bax involved in the binding with anti-apoptotic exapeptide (Bip) designed from Ku70, a subunit of the protein complex essential for non-homologous DNA repair but that inhibits also the Bax translocation to mitochondria. Since Bip suppresses apoptosis induced by several anti-cancer drugs, it appears relevant to achieve a better understanding of the structural and dynamical aspects that characterize the Bip-Bax complex in view of potential therapeutic implications. The present results show that the Bax region with the highest affinity for Bip is located in proximity of BH3 homology domain of Bax and also involves the alpha-helices 1 and 8. Moreover, the comparison of essential motions of Bax at 300 and 400 K before and after the formation of the complex with Bip evidences how the binding with the exa-peptide affects the collective motions of specific molecular districts of Bax considered to have functional relevance.

Amino Acid Sequence↗
PubMed2006

Kinetics and thermodynamics of type VIII beta-turn formation: a CD, NMR, and microsecond explicit molecular dynamics study of the GDNP tetrapeptide.

We report an experimental and theoretical study on type VIII beta-turn using a designed peptide of sequence GDNP. CD and NMR studies reveal that this peptide exists in equilibrium between type VIII beta-turn and extended conformations. Extensive MD simulations give a description of the free energy landscape of the peptide in which we retrieve the same two main conformations suggested by the experiments. The free energy difference between the two conformational states is very small and the transition between them occurs within a few kT at 300 K on a nanosecond timescale. The equilibrium is mainly driven by entropic contribution, which favors extended conformations over beta-turns. This confirms other theoretical studies showing that beta-turns are marginally stable in water solution because of the larger entropy of the extended state unless some stabilizing interactions exist. Our observations may be extended to any type of beta-turn and have important consequences for protein folding. A comparison of our MD and CD results also suggests a possible type VIII beta-turn CD signature indicated by one main band at 200 nm, close to that of random coil, and a fairly large shoulder at 220 nm. Last, our results clearly show that the XXXP motif can only fold into a type VIII beta-turn, which is consistent with its fairly strong propensity for this type of turn. This important finding may help for peptide design and is in line with recent studies on bioactive elastin peptides.

Circular Dichroism↗
PubMed2005

The mechanism of inhibition of the cyclin-dependent kinase-2 as revealed by the molecular dynamics study on the complex CDK2 with the peptide substrate HHASPRK.

Molecular dynamics (MD) simulations were used to explain structural details of cyclin-dependent kinase-2 (CDK2) inhibition by phosphorylation at T14 and/or Y15 located in the glycine-rich loop (G-loop). Ten-nanosecond-long simulations of fully active CDK2 in a complex with a short peptide (HHASPRK) substrate and of CDK2 inhibited by phosphorylation of T14 and/or Y15 were produced. The inhibitory phosphorylations at T14 and/or Y15 show namely an ATP misalignment and a G-loop shift (~5 A) causing the opening of the substrate binding box. The biological functions of the G-loop and GxGxxG motif evolutionary conservation in protein kinases are discussed. The position of the ATP gamma-phosphate relative to the phosphorylation site (S/T) of the peptide substrate in the active CDK2 is described and compared with inhibited forms of CDK2. The MD results clearly provide an explanation previously not known as to why a basic residue (R/K) is preferred at the P(2) position in phosphorylated S/T peptide substrates.

Adenosine Triphosphate↗
PubMed2000

Molecular dynamics of the KcsA K(+) channel in a bilayer membrane.

Molecular dynamics (MD) simulations of an atomic model of the KcsA K(+) channel embedded in an explicit dipalmitoylphosphatidylcholine (DPPC) phospholipid bilayer solvated by a 150 mM KCl aqueous salt solution are performed and analyzed. The model includes the KcsA K(+) channel, based on the recent crystallographic structure of, Science. 280:69-77), 112 DPPC, K(+) and Cl(-) ions, as well as over 6500 water molecules for a total of more than 40,000 atoms. Three K(+) ions are explicitly included in the pore. Two are positioned in the selectivity filter on the extracellular side and one in the large water-filled cavity. Different starting configurations of the ions and water molecules in the selectivity filter are considered, and MD trajectories are generated for more than 4 ns. The conformation of KcsA is very stable in all of the trajectories, with a global backbone root mean square (RMS) deviation of less than 1.9 A with respect to the crystallographic structure. The RMS atomic fluctuations of the residues surrounding the selectivity filter on the extracellular side of the channel are significantly lower than those on the intracellular side. The motion of the residues with aromatic side chains surrounding the selectivity filter (Trp(67), Trp(68), Tyr(78), and Tyr(82)) is anisotropic with the smallest RMS fluctuations in the direction parallel to the membrane plane. A concerted dynamic transition of the three K(+) ions in the pore is observed, during which the K(+) ion located initially in the cavity moves into the narrow part of the selectivity filter, while the other two K(+) ions move toward the extracellular side. A single water molecule is stabilized between each pair of ions during the transition, suggesting that each K(+) cation translocating through the narrow pore is accompanied by exactly one water molecule, in accord with streaming potential measurements (, Biophys. J. 55:367-371). The displacement of the ions is coupled with the structural fluctuations of Val(76) and Gly(77), in the selectivity filter, as well as the side chains of Glu(71), Asp(80), and Arg(89), near the extracellular side. Thus the mechanical response of the channel structure at distances as large as 10-20 A from the ions in the selectivity filter appears to play an important role in the concerted transition.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2003

On the evaluation and optimization of protein X-ray structures for pKa calculations.

The calculation of the physical properties of a protein from its X-ray structure is of importance in virtually every aspect of modern biology. Although computational algorithms have been developed for calculating everything from the dynamics of a protein to its binding specificity, only limited information is available on the ability of these methods to give accurate results when used with a particular X-ray structure. We examine the ability of a pKa calculation algorithm to predict the proton-donating residue in the catalytic mechanism of hen egg white lysozyme. We examine the correlation between the ability of the pKa calculation method to obtain the correct result and the overall characteristics of 41 X-ray structures such as crystallization conditions, resolution, and the output of structure validation software. We furthermore examine the ability of energy minimizations (EM), molecular dynamics (MD) simulations, and structure-perturbation methods to optimize the X-ray structures such that these give correct results with the pKa calculation algorithm. We propose a set of criteria for identifying the proton donor in a catalytic mechanism, and demonstrate that the application of these criteria give highly accurate prediction results when using unmodified X-ray structures. More specifically, we are able to successfully identify the proton donor in 85% of the X-ray structures when excluding structures with crystal contacts near the active site. Neither the use of the overall characteristics of the X-ray structures nor the optimization of the structure by EM, MD, or other methods improves the results of the pKa calculation algorithm. We discuss these results and their implications for the design of structure-based energy calculation algorithms in general.

Algorithms↗
PubMed2002

Molecular dynamics simulations of alpha2 --> 8-linked disialoside: conformational analysis and implications for binding to proteins.

Computational methods have played a key role in elucidating the various three-dimensional structures of oligosaccharides. Such structural information, together with other experimental data, leads to a better understanding of the role of oligosaccharide in various biological processes. The disialoside Neu5Ac-alpha2-->8-Neu5Ac appears as the terminal glycan in glycoproteins and glycolipids, and is known to play an important role in various events of cellular communication. Neurotoxins such as botulinum and tetanus require Neu5Ac-alpha2 --> 8-Neu5Ac for infecting the host. Glycoconjugates containing this disialoside and the enzymes catalyzing their biosynthesis are also regulated during cell growth, development, and differentiation. Unlike other biologically relevant disaccharides that have only two linkage bonds, the alpha2-->8-linked disialoside has four: C2-O, O-C8', C8'-C7', and C7'-C6'. The present report describes the results from nine 1 ns MD simulations of alpha2-->8-linked disialoside (Neu5Ac-alpha2-->8-Neu5Ac); simulations were run using GROMOS96 by explicitly considering the solvent molecules. Conformations around the O-C8' bond are restricted to the +sc/+ap regions due to stereochemical reasons. In contrast, conformations around the C2-O and C8'-C7' bonds were found to be largely unrestricted and all the three staggered regions are accessible. The conformations around the C7'-C6' bond were found to be in either the -sc or the anti region. These results are in excellent agreement with the available NMR and potential energy calculation studies. Overall, the disaccharide is flexible and adopts mainly two ensembles of conformations differing in the conformation around the C7'-C6' bond. The flexibility associated with this disaccharide allows for better optimization of intermolecular contacts while binding to proteins and this may partially compensate for the loss of conformational entropy that may be incurred due to disaccharide's flexibility.

Algorithms↗
PubMed2005

Structures and properties of self-assembled monolayers of bistable [2]rotaxanes on Au (111) surfaces from molecular dynamics simulations validated with experiment.

Bistable [2]rotaxanes display controllable switching properties in solution, on surfaces, and in devices. These phenomena are based on the electrochemically and electrically driven mechanical shuttling motion of the ring-shaped component, cyclobis(paraquat-p-phenylene) (CBPQT(4+)) (denoted as the ring), between a tetrathiafulvalene (TTF) unit and a 1,5-dioxynaphthalene (DNP) ring system located along a dumbbell component. When the ring is encircling the TTF unit, this co-conformation of the rotaxane is the most stable and thus designated the ground-state co-conformer (GSCC), whereas the other co-conformation with the ring surrounding the DNP ring system is less favored and so designated the metastable-state co-conformer (MSCC). We report here the structure and properties of self-assembled monolayers (SAMs) of a bistable [2]rotaxane on Au (111) surfaces as a function of surface coverage based on atomistic molecular dynamics (MD) studies with a force field optimized from DFT calculations and we report several experiments that validate the predictions. On the basis of both the total energy per rotaxane and the calculated stress that is parallel to the surface, we find that the optimal packing density of the SAM corresponds to a surface coverage of 115 A(2)/molecule (one molecule per 4 x 4 grid of surface Au atoms) for both the GSCC and MSCC, and that the former is more stable than the latter by 14 kcal/mol at the optimum packing density. We find that the SAM retains hexagonal packing, except for the case at twice the optimum packing density (65 A(2)/molecule, the 3 x 3 grid). For the GSCC and MSCC, investigated at the optimum coverage, the tilt of the ring with respect to the normal is theta = 39 degrees and 61 degrees, respectively, while the tilt angle of the entire rotaxane is psi = 41 degrees and 46 degrees , respectively. Although the tilt angle of the ring decreases with decreasing surface coverage, the tilt angle of the rotaxane has a maximum at 144 A(2)/molecule (the 4 x 5 grid/molecule) of 50 degrees and 51 degrees for the GSCC and MSCC, respectively. The hexafluorophosphate counterions (PF(6)(-)) stay localized around the ring during the 2 ns MD simulation. On the basis of the calculated density profile, we find that the thickness of the SAM is 40.5 A at the optimum coverage for the GSCC and 40.0 A for MSCC, and that the thicknesses become less with decreasing surface coverage. The calculated surface tension at the optimal packing density is 45 and 65 dyn/cm for the GSCC and MSCC, respectively. This difference suggests that the water contact angle for the GSCC is larger than for the MSCC, a prediction that is verified by experiments on Langmuir-Blodgett monolayers of amphiphilic [2]rotaxanes.

Journal Article↗
PubMed2004

Determination of enzyme mechanisms by molecular dynamics: studies on quinoproteins, methanol dehydrogenase, and soluble glucose dehydrogenase.

Molecular dynamics (MD) simulations have been carried out to study the enzymatic mechanisms of quinoproteins, methanol dehydrogenase (MDH), and soluble glucose dehydrogenase (sGDH). The mechanisms of reduction of the orthoquinone cofactor (PQQ) of MDH and sGDH involve concerted base-catalyzed proton abstraction from the hydroxyl moiety of methanol or from the 1-hydroxyl of glucose, and hydride equivalent transfer from the substrate to the quinone carbonyl carbon C5 of PQQ. The products of methanol and glucose oxidation are formaldehyde and glucolactone, respectively. The immediate product of PQQ reduction, PQQH- [-HC5(O-)-C4(=O)-] and PQQH [-HC5(OH)-C4(=O)-] converts to the hydroquinone PQQH2 [-C5(OH)=C4(OH)-]. The main focus is on MD structures of MDH * PQQ * methanol, MDH * PQQH-, MDH * PQQH, sGDH * PQQ * glucose, sGDH * PQQH- (glucolactone, and sGDH * PQQH. The reaction PQQ-->PQQH- occurs with Glu 171-CO2- and His 144-Im as the base species in MDH and sGDH, respectively. The general-base-catalyzed hydroxyl proton abstraction from substrate concerted with hydride transfer to the C5 of PQQ is assisted by hydrogen-bonding to the C5=O by Wat1 and Arg 324 in MDH and by Wat89 and Arg 228 in sGDH. Asp 297-COOH would act as a proton donor for the reaction PQQH(-)-->PQQH, if formed by transfer of the proton from Glu 171-COOH to Asp 297-CO2- in MDH. For PQQH-->PQQH2, migration of H5 to the C4 oxygen may be assisted by a weak base like water (either by crystal water Wat97 or bulk solvent, hydrogen-bonded to Glu 171-CO2- in MDH and by Wat89 in sGDH).

Alcohol Oxidoreductases↗
PubMed2005

Limited flexibility of lactose detected from residual dipolar couplings using molecular dynamics simulations and steric alignment methods.

The conformational flexibility of lactose in solution has been investigated by residual dipolar couplings (RDCs). One-bond carbon-proton and proton-proton coupling constants have been measured in two oriented media and interpreted in combination with molecular dynamics simulations (MD). Two different approaches, known as PALES (Zweckstetter et al., J. Am. Chem. Soc. 2000, 122, 3791-3792) and TRAMITE (Azurmendi et al., J. Am. Chem. Soc. 2002, 124, 2426-2427), have been used to determine the alignment tensor from a shape-induced alignment model with the oriented medium. The steric alignment of the structures from several MD trajectories has provided ensemble averaged RDCs that have been compared with the experimental ones. The obtained results reveal the almost exclusive presence of a major low energy region defined as syn-phi/syn-psi (> 97%), for which sampling occurs in a dynamic manner. This result satisfactorily agrees with that determined by standard NOE-based methods.

Carbohydrate Conformation↗
PubMed2002

Molecular dynamics simulations of glycoclusters and glycodendrimers.

Protein-carbohydrate recognition plays a crucial role in a wide range of biological processes, required both for normal physiological functions and the onset of disease. Nature uses multivalency in carbohydrate-protein interactions as a strategy to overcome the low affinity found for singular binding of an individual saccharide epitope to a single carbohydrate recognition domain of a lectin. To mimic the complex multi-branched oligosaccharides found in glycoconjugates, which form the structural basis of multivalent carbohydrate-protein interactions, so-called glycoclusters and glycodendrimers have been designed to serve as high-affinity ligands of the respective receptor proteins. To allow a rational design of glycodendrimer-type molecules with regard to the receptor structures involved in carbohydrate recognition, a deeper knowledge of the dynamics of such molecules is desirable. Most glycodendrimers have to be considered highly flexible molecules with their conformational preferences most difficult to elucidate by experimental methods. Longtime molecular dynamics (MD) simulations with inclusion of explicit solvent molecules are suited to explore the conformational space accessible to glycodendrimers. Here, a detailed geometric and conformational analysis of 15 glycodendrimers and glycoclusters has been accomplished, which differ with regard to their core moieties, spacer characteristics and the type of terminal carbohydrate units. It is shown that the accessible conformational space depends strongly on the structural features of the core and spacer moieties and even on the type of terminating sugars. The obtained knowledge about possible spatial distributions of the sugar epitopes exposed on the investigated hyperbranched neoglycoconjugates is detailed for all examples and forms important information for the interpretation and prediction of affinity data, which can be deduced from biological testing of these multivalent neoglycoconjugates.

Carbohydrate Conformation↗
PubMed1998

The high degree of internal flexibility observed for an oligomannose oligosaccharide does not alter the overall topology of the molecule.

The conformational properties of oligosaccharides are important in determining their biological properties, such as recognition by proteins. The structural and dynamic properties of many oligosaccharides are poorly understood both because of a lack of experimental data (usually obtained from solution NMR parameters) and because of gross approximations frequently invoked in theoretical models. To characterise the oligomannose oligosaccharide Man,GlcNAc2 we have acquired a more extensive NMR data set and performed the first unrestrained molecular dynamics (MD) simulation in water of this large oligosaccharide (employing the GLYCAM_93 parameter set with the AMBER force field). Good agreement is seen between the computed dynamics data and the results of both an isolated spin pair (ISPA) analysis of short mixing time NOE data and NOE build-up curves for mixing times from 100 to 2000 ms. The number of experimental conformational constraints obtained in this study are in principle sufficient to fully define a rigid structure. The fact that this could not be done indicates a high degree of internal flexibility and/or the presence of multiple conformations about the glycosidic linkages. Independently, the same conclusions are reached from an analysis of the MD results. In addition, the theoretical results allow the overall topology of the molecule and its intra-molecular and solvent-mediated hydrogen bonding pattern to be defined. Extensive re-organisation of solvent and inter-residue hydrogen bonds is shown to be required for significant conformational changes to occur, resulting in relatively long life-times for distinct glycosidic linkage conformations, despite the high local flexibility of the glycosidic linkages. This factor is also seen in the overall topology of the molecule, where the considerable internal flexibility is not translated into gross changes in structure. The control exerted by the solvent over both the flexibility and overall topology of an oligosaccharide has important implications for recognition processes and for the conformational properties of glycans attached to glycoproteins.

Acetylglucosamine↗
PubMed2006

Characterization of de novo four-helix bundles by molecular dynamics simulations.

We have investigated the structure and dynamics of three cavitand-based four-helix bundles (caviteins) by computer simulation. In these systems, designed de novo, each of the four helices contain the identical basis sequence EELLKKLEELLKKG (N1). Each cavitein consists of a rigid macrocycle (cavitand) with four aryl linkages, to each of which is connected an N1 peptide by means of a linker peptide. The three caviteins studied here differ only in the linker peptide, which consist of one, two, or three glycine residues. Previous experimental work has shown that these systems exhibit very different behavior in terms of stability and oligomerization states despite the small differences in the linker peptide. Given that to date no three-dimensional structure is available for these caviteins, we have undertaken a series of molecular dynamics (MD) simulations in explicit water to try to rationalize the large differences in the experimentally observed behavior of these systems. Our results provide insight, for the first time, into why and how the cavitein with a single glycine linker forms dimers. In addition, our results indicate why although the two- and three-glycine-linked caviteins have similar stabilities, they have different native-like characteristics: the cavitein with three glycines can form a supercoiled helix, whereas the one with two glycines cannot. These findings may provide a useful guide in the rational de novo design of novel proteins with finely tunable structures and functions in the future.

Amino Acid Sequence↗
PubMed2001

Molecular dynamics simulations of the denaturation and refolding of an RNA tetraloop.

Tetraloops are very abundant structural elements of RNA that are formed by four nucleotides in a hairpin loop which is closed by a double stranded helical stem with some Watson-Crick base pairs. A tetraloop r(GCGAAGGC) was identified from the crystal structure of the central domain of 16S rRNA (727-730) in the Thermus thermophilus 30S ribosomal complex. The crystal structure of the 30S complex includes a total of 104 nucleotides from the central domain of the 16S rRNA and three ribosomal proteins S6, S15 and S18. Independent biochemical experiments have demonstrated that protein S15 plays the role in initiating the formation of the central domain of this complex. In the crystal, the tetraloop interacts with the protein S15 at two sites: one of them is associated with hydrogen bond interactions between residue His50 and nucleotide G730, and the other is associated with the occurrence of residue Arg53 beside A728. This paper uses molecular dynamics (MD) simulations to investigate the protein-dependent structural stability of the tetraloop and demonstrates the folding pathway of this tetraloop via melting denaturation and its subsequent refolding. Three important results are derived from these simulations: (i) The stability of nucleotide A728 appears to be protein dependent. Without the interaction with S15, A728 flips away from stacking with A729. (ii) The melting temperature demonstrated by the simulations is analogous to the results of thermodynamic experiments. In addition, the simulated folding of the tetraloop is stepwise: the native shape of the backbone is formed first; this is then followed by the formation of the Watson- Crick base pairs in the stem; and finally the hydrogen bonds and base stacking in the loop are formed. (iii) The tetraloop structure is similar to the crystal structure at salt concentrations of 0.1 M and 1.0 M used for the simulations, but the refolded structure at 0.1 M salt is more comparable to the crystal structure than at 1.0 M. The results from the simulations using both the Generalized Born continuum model and explicit solvent model (Particle Mesh Ewald) generate a similar pathway for unfolding/refolding of the tetraloop.

Arginine↗
PubMed2007

Structural and dynamic properties of concentrated alkali halide solutions: a molecular dynamics simulation study.

The physicochemical properties of alkali halide solutions have long been attributed to the collective interactions between ions and water molecules in the solution, yet the structure of water in these systems and its effect on the equilibrium and dynamic properties of these systems are not clearly understood. Here, we present a systematic view of water structure in concentrated alkali halide solutions using molecular dynamics simulations. The results of the simulations show that the size of univalent ions in the solution has a significant effect on the dynamics of ions and other transport properties such as the viscosity that are correlated with the structural properties of water in aqueous ionic solution. Small cations (e.g., Li+) form electrostatically stabilized hydrophilic hydration shells that are different from the hydration shells of large ions (e.g., Cs+) which behave more like neutral hydrophobic particles, encapsulated by hydrogen-bonded hydration cages. The properties of solutions with different types of ion solvation change in different ways as the ion concentration increases. Examples of this are the diffusion coefficients of the ions and the viscosities of solutions. In this paper we use molecular dynamics (MD) simulations to study the changes in the equilibrium and transport properties of LiCl, RbCl, and CsI solutions at concentrations from 0.22 to 3.97 M.

Journal Article↗