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PubMed1996

Molecular dynamics: deciphering the data.

The dynamic behaviour of molecules is important in determining their activity. Molecular dynamics (MD) simulations give a detailed description of motion, from small fluctuations to conformational transitions, and can include solvent effects. However, extracting useful information about conformational motion from a trajectory is not trivial. We have used digital signal-processing techniques to characterise the motion in MD simulations, including: calculating the frequency distribution, applying filtering functions, and extraction of vectors defining the characteristic motion for each frequency in an MD simulation. We describe here some typical results obtained for peptides and proteins. The nature of the low-frequency modes of motion, as obtained from MD and normal mode (NM) analysis, of Ace-(Ala)31-Nma and of a proline mutant is discussed. Low-frequency modes extracted from the MD trajectories of Rop protein and phospholipase A2 reveal characteristic motions of secondary structure elements, as well as concerned motions that are of significance to the protein's biological activity. MD simulations are also used frequently as a tool for conformational searches and for investigating protein folding/unfolding. We have developed a novel method that uses time-domain filtering to channel energy into conformational motion and thus enhance conformational transitions. The selectively enhanced molecular dynamics method is tested on the small molecule hexane.

Animals↗
PubMed2002

On the Debye-Waller factor of hexagonal ice: a computer simulation study.

We investigate by molecular dynamics (MD) simulations the temperature dependence of the Debye-Waller (DW) factor of hexagonal ice with 25 different proton-disordered configurations. Each initial configuration is composed of 288 water molecules with no net dipole moment. The intermolecular interaction of water is described by TIP4P potential. Each production run of the simulation is 15 ns or longer. We observe a change in slope of the DW factor around 200 K, which cannot be explained within the framework of either classical or quantum harmonic approximation. Configurations generated by MD simulations are subjected to the steepest descent energy minimization. Analysis of the local energy minimum structures reveals that water molecules above 200 K jump to other lattice sites via some local energy minimum structures which contain some water molecules sitting on the locations other than the lattice sites. As time evolves, these defect molecules move back and forth to the lattice sites yielding defect-free structures. Those motions are responsible for the unusual increase in the DW factor at high temperatures. In making a transition from an energy-minimum structure to another one, a small number of water molecules are involved in a highly cooperative fashion. The larger DW factor at higher temperature arises from jump-like motions of water molecules among these locally stable configurations which may or may not be a family of the proton-disordered ice forms satisfying the "ice rule".

Computer Simulation↗
PubMed1992

Conformational states of a TT mismatch from molecular dynamics simulation of duplex d (CGCGATTCGCG).

The TT mismatch region in duplex d (CGCGATTCGCG) was studied using a 500-ps molecular dynamics (MD) simulation in water, and a series of 1-ps MD simulations and energy minimizations in vacuum. The DNA maintained its duplex structure, although the mismatch region showed significantly higher flexibility than the GC regions. The predominant conformation in the 500-ps MD simulation involved an average -42 degrees propeller twist between T6 and T'6, and a -22 degree buckle between A5 and T'7. One hydrogen bond was formed between T6 and T'6, and another between T6 and the O2 of T'7, with both Watson-Crick hydrogen bonds between A5 and T'7 remaining intact. The minimizations resulted in conformations with the equivalent hydrogen-bonding pattern, as well as ones with "wobble pair" hydrogen bonds between T6 and T'6. However, the wobble pair conformation was found to be unstable in the water simulation.

Base Sequence↗
PubMed2005

Metabolic regio- and stereoselectivity of cytochrome P450 2D6 towards 3,4-methylenedioxy-N-alkylamphetamines: in silico predictions and experimental validation.

A series of 3,4-methylenedioxy-N-alkylamphetamines (MDAAs) were automatically docked and subjected to molecular dynamics (MD) simulations in a cytochrome P450 2D6 (CYP2D6) protein model. The predicted substrate binding orientations, sites of oxidation, and relative reactivities were compared to the experimental data of wild-type and Phe120Ala mutant CYP2D6. Automated docking results were not sufficient to accurately rationalize experimental binding orientations of 3,4-methylenedioxy-N-methylamphetamine (MDMA) in the two enzymes as measured with spin lattice relaxation NMR. Nevertheless, the docking results could be used as starting structures for MD simulations. Predicted binding orientations of MDMA and sites of oxidation of the MDAAs derived from MD simulations matched well with the experimental data. It appeared the experimental results were best described in MD simulations considering the nitrogen atoms of the MDAAs in neutral form. Differences in regioselectivity and stereoselectivity in the oxidative metabolism of the MDAAs by the Phe120Ala mutant CYP2D6 were correctly predicted, and the effects of the Phe120Ala mutation could be rationalized as well.

Amphetamines↗
PubMed2001

The xenograft antigen bound to Griffonia simplicifolia lectin 1-B(4). X-ray crystal structure of the complex and molecular dynamics characterization of the binding site.

The shortage of organs for transplantation into human patients continues to be a driving force behind research into the use of tissues from non-human donors, particularly pig. The primary barrier to such xenotransplantation is the reaction between natural antibodies present in humans and Old World monkeys and the Gal alpha(1-3)Gal epitope (xenograft antigen, xenoantigen) found on the cell surfaces of the donor organ. This hyperacute immune response leads ultimately to graft rejection. Because of its high specificity for the xenograft antigen, isolectin 1-B(4) from Griffonia simplicifolia (GS-1-B(4)) has been used as an immunodiagnostic reagent. Furthermore, haptens that inhibit natural antibodies also inhibit GS-1-B(4) from binding to the xenoantigen. Here we report the first x-ray crystal structure of the xenograft antigen bound to a protein (GS-1-B(4)). The three-dimensional structure was determined from orthorhombic crystals at a resolution of 2.3 A. To probe the influence of binding on ligand properties, we report also the results of molecular dynamics (MD) simulations on this complex as well as on the free ligand. The MD simulations were performed with the AMBER force-field for proteins augmented with the GLYCAM parameters for glycosides and glycoproteins. The simulations were performed for up to 10 ns in the presence of explicit solvent. Through comparison with MD simulations performed for the free ligand, it has been determined that GS-1-B(4) recognizes the lowest energy conformation of the disaccharide. In addition, the x-ray and modeling data provide clear explanations for the reported specificities of the GS-1-B(4) lectin. It is anticipated that a further understanding of the interactions involving the xenograft antigen will help in the development of therapeutic agents for application in the prevention of hyperacute xenograft rejection.

Animals↗
PubMed2003

Bridging structural biology and genetics by computational methods: an investigation into how the R774C mutation in the AR gene can result in complete androgen insensitivity syndrome.

Recent structural studies of the ligand-binding domain (LBD) of the androgen receptor (AR) have raised more questions than answers, as most of the known pathogenic mutations of the AR gene causing androgen insensitivity syndrome (AIS) are not in the ligand-binding pocket. In this study, we have investigated one such pathogenic mutation, by examining details of its altered atomic structure using a computational technique of molecular dynamics (MD) simulations extended over 4 ns, effectively creating a 4D structural model. The mutation R774C, which is in the LBD of the AR gene, causes complete AIS (CAIS), producing ARs that have a unique thermolabile profile, being thermostable at 22 degrees C but thermolabile at 37 degrees C. We have therefore investigated this mutation by MD simulations at 293 K (20 degrees C), 300 K (27 degrees C), and 310 K (37 degrees C). The MD simulations indicate that: 1) the mutation causes local structural distortions, which result in changes in the shape of the ligand-binding pocket; 2) the mutation alters the dynamic nature of the protein and results in a more diverse conformational distribution of the ligand-binding pocket; and 3) the effect of the mutation on AR structure could be largely reversed by lowering the temperature at which the MD simulations were conducted. These results therefore strongly support the biochemical data, e.g., the mutants' inability to form AR-ligand complexes at 37 degrees C and its characteristic reversible thermolability, clearly indicating the value of such computational methods.

Androgen-Insensitivity Syndrome↗
PubMed2002

Development and validation of an integrated computational approach for the study of ionic species in solution by means of effective two-body potentials. The case of Zn2+, Ni2+, and Co2+ in aqueous solutions.

In this paper we have developed an effective computational procedure for the structural and dynamical investigation of ions in aqueous solutions. Quantum mechanical potential energy surfaces for the interaction of a transition metal ion with a water molecule have been calculated taking into account the effect of bulk solvent by the polarizable continuum model (PCM). The effective ion-water interactions have been fitted by suitable analytical potentials, and have been utilized in molecular dynamics (MD) simulations to obtain structural and dynamical properties of the ionic aqueous solutions. This procedure has been successfully applied to the Co2+-H2O open-shell system and, for the first time, Co-oxygen and Co-hydrogen pair potential functions have been determined and employed in MD simulations. The reliability of the whole procedure has been assessed by applying it also to the Zn2+ and Ni2+ aqueous solutions, and the structural and dynamical properties of the three systems have been calculated by means of MD simulations and have been found to be in very good agreement with experimental results. The structural parameters of the first solvation shells issuing from the MD simulations provide an effective complement to extended X-ray absorption fine structure (EXAFS) experiments.

Journal Article↗
PubMed1994

Molecular dynamics simulations of oligosaccharides and their conformation in the crystal structure of lectin-carbohydrate complex: importance of the torsion angle psi for the orientation of alpha 1,6-arm.

The conformation of the heptasaccharide Man-alpha 1,6-(Man-alpha 1,3)(Xyl-beta 1,2)-Man-beta 1,4-GlcNAc2-beta 1,4-(L- Fuc-alpha 1,3)-GlcNAc1, the carbohydrate moiety of Erythrina corallodendron lectin (EcorL), the hexasaccharide Man-alpha 1,6-(Man-alpha 1,3) (GlcNAc-beta 1,4)-Man-beta 1,4-GlcNAc-beta 1,4-GlcNAc and their disaccharide fragments have been studied by molecular dynamics (MD) simulations for 1000 ps with different initial conformations. In the isolated heptasaccharide, the most frequently accessed conformation during MD has a psi value of 180 degrees around Man-alpha 1,6-Man linkage. This conformation is stabilized by the formation of a hydrogen bond between the carbonyl oxygen of GlcNAc2 with the O3/O4 hydroxyls of the alpha 1,6-linked mannose residue. The conformation of the heptasaccharide found in the crystal structure of the EcorL-lactose complex (Shaanan et al., Science, 254, 862, 1991), that has a psi value of approximately 76 degrees around Man-alpha 1,6-Man linkage, is accessed, although less frequently, during MD of the isolated oligosaccharide. The phi, psi, chi = 58 degrees, -134 degrees, -60 degrees conformation around Man-alpha 1,6-Man fragment observed in the crystal structure of the Lathyrus ochrus lectin complexed with a biantennary octasaccharide (Table I in Homans, S.W., Glycobiology, 3, 551, 1993) has also been accessed in the present MD simulations. These psi values for the alpha 1,6-linkage, which are observed in the protein-carbohydrate crystal structures and are accessed in the MD simulations, though occasionally, have not been predicted from NMR studies. Furthermore, these different values of psi lead to significantly different orientations of the alpha 1,6-arm for the same value of chi. This contrasts with the earlier predictions that only different values of chi can bring about significant changes in the orientation of the alpha 1,6-arm. The MD simulations also show that the effects of bisecting GlcNAc or beta 1,2-xylose are very similar on the alpha 1,3-arm and slightly different on the alpha 1,6-arm.

Carbohydrate Conformation↗
PubMedDate not supplied

Molecular dynamics simulations of aqueous pullulan oligomers.

Molecular dynamics (MD) simulations have been used to model small-angle X-ray scattering (SAXS) data on aqueous solutions of four oligomeric segments of the glucan pullulan: the trimer G(3) (comprising one polymer repeating unit), the hexamer (G(3))(2), the nonamer (G(3))(3), and the dodecamer (G(3))(4). The AMBER force field was used in conjunction with the GB/SA continuum solvation model to calculate both the mean global dimensions of the oligomers from the limiting small angle scattering behavior and the shorter range structural information implicit in the Debye scattering function at larger scattering angles. This same force field and solvation treatment were employed earlier by Liu et al. (Macromolecules 1999, 32, 8611-8620) with apparent success in a rotational isomeric state (RIS) treatment of the same experimental data. The present work discloses that, despite numerical success in modeling the SAXS data, the RIS treatment, which includes only the interactions within dimeric segments of the polymer chain, fails to account accurately for excluded volume effects at the range of 3-12 sugar residues in the polymer backbone. It is suggested that MD simulations using continuum solvation models can be used to circumvent errors inherent in the computationally efficient RIS treatments of polymer nano- and picosecond dynamics while at the same time avoiding the heavy computational requirements of all-atom methods.

Carbohydrate Conformation↗
PubMed2005

Theoretical study of the stability of lithium atoms in alpha-rhombohedral boron.

The stability of lithium atoms in alpha-rhombohedral boron was investigated by first-principles calculations of total energies and molecular dynamics (MD) simulations. In the case of a low concentration (1.03 at. %), Li at the center of the icosahedral B12 site (the I-site) had a negative binding energy, which suggests Li at the I-site is unstable. However, MD simulations at temperatures below 750 K indicated that Li is still confined in the B12 cage under these conditions, which means Li at the I-site is metastable. Over 800 K, Li began to move away from the B12 site and settled at the tetrahedral site (the T-site) or at the octahedral site (the O-site). Li at the T-site also had a negative binding energy, but MD simulations indicated it was metastable up to 1400 K and did not move to other sites. Li at the O-site was energetically the most favorable, having a positive binding energy. In the case of a high concentration (7.69 at. %), the I-site changed to an unstable saddle point. At this concentration, the T-site was metastable and the O-site became the most stable. In MD simulations at 1400 K, Li atoms at the O-site never jumped to other sites regardless of concentration. Considering these facts, the diffusion coefficient of Li in alpha-rhombohedral boron would have to be very small below 1400 K.

Journal Article↗
PubMed1995

Characterization of the internal motions of Escherichia coli ribonuclease HI by a combination of 15N-NMR relaxation analysis and molecular dynamics simulation: examination of dynamic models.

The backbone dynamics of Escherichia coli ribonuclease HI (RNase HI) in the picosecond to nanosecond time scale were characterized by a combination of measurements of 15N-NMR relaxation (T1, T2, and NOE), analyzed by a model-free approach, and molecular dynamics (MD) simulation in water. The MD simulations in water were carried out with long-range Coulomb interactions to avoid the artificial fluctuation caused by the cutoff approximation. The model-free analysis of the 15N-NMR relaxation indicated that RNase HI has a rotational correlation time of 10.9 ns at 27 degrees C. The generalized order parameter (S2) for the internal motions varied from 0.15 to 1.0, with an average value of 0.85, which is much larger than that of the RNase H domain of HIV-1 reverse transcriptase (0.78). Large internal motions (small order parameters) were observed in the N-terminal region (Leu2-Lys3), the loop between beta-strands A and B (Cys13-Gly15), the turn between alpha-helix I and beta-strand D (Glu61, His62), the loop between beta-strand D and alpha-helix II (Asp70-Tyr71), the loop between alpha-helices III and IV (Ala93-Lys96), the loop between beta-strand E and alpha-helix V (Gly123-His127), and the C-terminal region (Gln152-Val155). The effective correlation time observed in these regions varied from 0.45 ns (Glu61, Lys96) to 2.2 ns (Leu14). The order parameters calculated from the MD agreed well with those from the NMR experiment, with a few exceptions. The distributions of most of the backbone N-H vectors obtained by MD are approximately consistent with the diffusion-in-a-cone model. These distributions, however, were elliptic, with a long axis perpendicular to the plane defined by the N-H and N-C alpha vectors. Distributions supporting the axial fluctuation model or the jump-between-two-cones model were also observed in the MD simulation.

Binding Sites↗
PubMed2004

Probing the Ser-Ser-Lys catalytic triad mechanism of peptide amidase: computational studies of the ground state, transition state, and intermediate.

Peptide amidase (Pam), a hydrolytic enzyme that belongs to the amidase signature (AS) family, selectively catalyzes the hydrolysis of the C-terminal amide bond (CO-NH(2)) of peptides. The recent availability of the X-ray structures of Pam, fatty acid amide hydrolase, and malonamidase E2 has led to the proposal of a novel Ser-Ser-Lys catalytic triad mechanism for the amide hydrolysis by the AS enzymes. The molecular dynamics (MD) simulations using the CHARMM force field were performed to explore the catalytic mechanism of Pam. The 1.8 A X-ray crystal structure of Pam in complex with the amide analogue of chymostatin was chosen for the initial coordinates for the MD simulations. The five systems that were investigated are as follows: (i) enzyme.substrate with Lys123-NH(2), (ii) enzyme.substrate with Lys123-NH(3)(+), (iii) enzyme.substrate with Lys123-NH(3)(+) and Ser226-O(-), (iv) enzyme.transition state, and (v) enzyme.tetrahedral intermediate. Our data support the presence of the hydrogen bonding network among the catalytic triad residues, Ser226, Ser202, and Lys123, where Ser226 acts as the nucleophile and Ser202 bridges Ser226 and Lys123. The MD simulation supports the catalytic role of the crystallographic waters, Wat1 and Wat2. In all the systems that have been studied, the backbone amide nitrogens of Asp224 and Thr223 create an oxyanion hole by hydrogen bonding to the terminal amide oxygen of the substrate, and stabilize the oxyanion tetrahedral intermediate. The results from both our computational investigation and previously published experimental pH profile support two mechanisms. In a mechanism that is relevant at lower pH, the Lys123-NH(3)(+)-Ser202 dyad provides structural support to the catalytic residue Ser226, which in turn carries out a nucleophilic attack at the substrate amide carbonyl in concert with Wat1-mediated deprotonation and stabilization of the tetrahedral transition state by the oxyanion hole. In the mechanism operating at higher pH, the Lys123-NH(2)-Ser202 catalytic dyad acts as a general base to assist addition of Ser226 to the substrate amide carbonyl. The results from the MD simulation of the tetrahedral intermediate state show that both Ser202 and Lys123 are possible candidates for protonation of the leaving group, NH(2), to form the acyl-enzyme intermediate.

Amidohydrolases↗
PubMed2005

Electric field induced switching behaviors of monolayer-modified silicon surfaces: surface designs and molecular dynamics simulations.

Electric field induced switching behaviors of a series of low-density omega-carboxyalkyl modified H-Si(111) and the mixed omega-carboxyalkyl/alkyl covered H-Si(111) have been simulated by using molecular dynamics (MD) simulation techniques. The external electric fields may drive surface-confined molecules to reversibly change conformations between the all-trans (switching "on") and the mixed trans-gauche (switching "off") states. Such surfaces switch wettabilities between the hydrophilic state and the moderately hydrophobic state. It has been found in broad ranges of intensities of applied electric fields, -2.0 x 10(9) V/m < or = E(down) < or = 0 and 1.8 x 10(9) V/m < or = E(up) < or = 7.3 x 10(9) V/m, both the low-density (11.1%-33.3%) omega-carboxyalkyl and the mixed omega-carboxyalkyl/alkyl (in mole fraction of 0.4 < or = N(carboxyalkyl) : N(alkyl) < or = 3.0) monolayers covering H-Si(111) exhibit conformational switching in the aqueous medium. The critical intensity of the electric field, E(up) = 1.8 x 10(9) V/m, which is required to trigger the switches is observed by our MD simulations and further rationalized by a thermodynamical model. Some important factors in the control of switching performances, such as the steric hindrances, the formation of the electric double layer at the monolayer/electrolyte solution interface, the hydration effects of carboxylate anions, the components of surrounding electrolyte solutions, as well as the rigidity of surface-confined chains are elucidated. The lower ionic strength and additions of acetonitrile molecules in the surrounding aqueous solution can reduce the value of critical intensity of the electric field and hence facilitate the realization of switching. Some practical considerations in construction and optimum design of switching surfaces are also suggested.

Journal Article↗
PubMed2003

Gramicidin A channel as a test ground for molecular dynamics force fields.

We use the well-known structural and functional properties of the gramicidin A channel to test the appropriateness of force fields commonly used in molecular dynamics (MD) simulations of ion channels. For this purpose, the high-resolution structure of the gramicidin A dimer is embedded in a dimyristoylphosphatidylcholine bilayer, and the potential of mean force of a K(+) ion is calculated along the channel axis using the umbrella sampling method. Calculations are performed using two of the most common force fields in MD simulations: CHARMM and GROMACS. Both force fields lead to large central barriers for K(+) ion permeation, that are substantially higher than those deduced from the physiological data by inverse methods. In long MD simulations lasting over 60 ns, several ions are observed to enter the binding site but none of them crossed the channel despite the presence of a large driving field. The present results, taken together with many earlier studies, highlights the shortcomings of the standard force fields used in MD simulations of ion channels and calls for construction of more appropriate force fields for this purpose.

Binding Sites↗
PubMed2005

Coarse-grained modeling of the actin filament derived from atomistic-scale simulations.

A coarse-grained (CG) procedure that incorporates the information obtained from all-atom molecular dynamics (MD) simulations is presented and applied to actin filaments (F-actin). This procedure matches the averaged values and fluctuations of the effective internal coordinates that are used to define a CG model to the values extracted from atomistic MD simulations. The fluctuations of effective internal coordinates in a CG model are computed via normal-mode analysis (NMA), and the computed fluctuations are matched with the atomistic MD results in a self-consistent manner. Each actin monomer (G-actin) is coarse-grained into four sites, and each site corresponds to one of the subdomains of G-actin. The potential energy of a CG G-actin contains three bonds, two angles, and one dihedral angle; effective harmonic bonds are used to describe the intermonomer interactions in a CG F-actin. The persistence length of a CG F-actin was found to be sensitive to the cut-off distance of assigning intermonomer bonds. Effective harmonic bonds for a monomer with its third nearest neighboring monomers are found to be necessary to reproduce the values of persistence length obtained from all-atom MD simulations. Compared to the elastic network model, incorporating the information of internal coordinate fluctuations enhances the accuracy and robustness for a CG model to describe the shapes of low-frequency vibrational modes. Combining the fluctuation-matching CG procedure and NMA, the achievable time- and length scales of modeling actin filaments can be greatly enhanced. In particular, a method is described to compute the force-extension curve using the CG model developed in this work and NMA. It was found that F-actin is easily buckled under compressive deformation, and a writhing mode is developed as a result. In addition to the bending and twisting modes, this novel writhing mode of F-actin could also play important roles in the interactions of F-actin with actin-binding proteins and in the force-generation process via polymerization.

Actins↗
PubMed1999

Constructing the suitable initial configuration of the membrane-protein system in molecular dynamics simulations.

A method for constructing the suitable initial configuration of the membrane-protein system for molecular dynamics (MD) simulations is presented. This method could provide some hydrated initial configurations and help us to determine the best surface area of the system by contracting the surface area and comparing the optimized lowest energy of the system by energy minimization. The gramicidin A (GA) channel in;the fully hydrated dimyristoylphosphatidylcholine (DMPC) bilayer was used as our model. Three configurations with different surface areas were selected and applied for one 400 ps and two 300 ps MD simulations at constant pressure and temperature. All simulations were fairly stable without any constraints. Through analysis of the MD trajectories we found that the system with the best surface area was more stable than the other two systems, whose sizes were changed in the simulations. Further analysis of the bilayer normal length and the order parameters of the lipid alkyl tails indicates that the system with the best surface area shows some characteristics of the L(alpha) phase, while both the smaller and the larger size systems have distinct deviations from the L(alpha) phase that we expect. This illustrates that the correct surface area and the suitable initial configuration have an important influence on the phase of the membrane in the MD simulation. In addition, by comparing the root mean square differences of GA relative to the initial structure and interaction energy between different components of the system for all three systems, we find that the state of the DMPC bilayer has exerted a significant influence on the structure of GA. All these results demonstrate the validity of our method for constructing the initial configuration of the membrane-protein system for MD simulations.

Carbon↗
PubMed2005

Conformational transition of amyloid beta-peptide.

The amyloid beta-peptides (Abetas), containing 39-43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of Abeta(40), 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an alpha-helix to beta-sheet conformational transition for Abeta(40) was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with beta-sheet components were observed as intermediates in the unfolding pathway of Abeta(40). Four glycines (G(25), G(29), G(33), and G(37)) are important for Abeta(40) to form beta-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the beta-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of Abeta(40) is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic feature revealed by our MD simulations rationalized several experimental observations for Abeta(40) aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of Abeta and amyloid fibril formation.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2001

Oligosaccharides display both rigidity and high flexibility in water as determined by 13C NMR relaxation and 1H,1H NOE spectroscopy: evidence of anti-phi and anti-psi torsions in the same glycosidic linkage.

The trisaccharide beta-D-Glcp-(1-->2)-beta-D-Glcp-(1-->3)-alpha-D-Glcp-OMe has been investigated by molecular dynamics (MD) simulations and NMR experiments in water. 13C spin-lattice (T1) and spin-spin (T2) relaxation times, together with 1H,13C NOE data were measured at two magnetic field strengths (9.4 and 14.1 T) in a 277 K D2O solution. Relaxation data interpreted by means of the model-free formalism revealed a rigid (S2 approximately 0.9) oligosaccharide tumbling in solution. 1H,1H Cross-relaxation rates were determined at 600 MHz by 1D DPFGSE NOESY and T-ROESY experiments, which provided high quality data and subsequently proton-proton distances within the trisaccharide. The presence of anti conformers at both torsions of a glycosidic linkage is demonstrated for the first time. MD simulations were carried out to facilitate analysis of the NOE data. In total, 15 simulations-starting from five different conformational states--were performed, with production runs of up to 10 ns, resulting in 83 ns of oligosaccharide dynamics in water. anti Conformers were populated to different degrees in the simulations, especially at the phi2 torsion angle. By combining the results from the NOE experiments and the MD simulations, the anti conformers at the (1-->2)-linkage were quantified as 7% anti-phi2 and 2% anti-psi2, revealing a highly flexible trisaccharide in which large conformational changes occur. From the MD simulations, interresidue hydrogen bonding, from HO2" to O2 or O3, was significantly populated (approximately 40%) in both of the anti conformational states. The contentious issue over rigidity versus flexibility in oligosaccharides has thus been thoroughly examined, showing that the dynamics should be taken into account for a relevant description of the molecular system.

Carbohydrate Conformation↗