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PubMed1997

The crystal and molecular structures of cellulose I and II.

The paper describes molecular dynamics (MD) simulations on the crystal structures of the Ibeta and II phases of cellulose. Structural proposals for each of these were made in the 1970s on the basis of X-ray diffraction data. However, due to the limited resolution of these data some controversies remained and details on hydrogen bonding could not be directly obtained. In contrast to structure factor amplitudes in X-ray diffraction, energies, as obtained from MD simulations, are very sensitive to the positions of the hydroxyl hydrogen atoms. Therefore the latter technique is very suitable for obtaining such structural details. MD simulations of the Ibeta phase clearly shows preference for one of the two possible models in which the chains are packed in a parallel orientation. Only the parallel-down mode (in the definition of Gardner and Blackwell (1974) J Biopolym 13: 1975-2001) presents a stable structure. The hydrogen bonding consists of two intramolecular hydrogen bonds parallel to the glycosidic linkage for both chains, and two intralayer hydrogen bonds. The layers are packed hydrophobically. All hydroxymethyl group are positioned in the tg conformation. For the cellulose II form it was found that, in contrast to what seemed to emerge from the X-ray fibre diffraction data, both independent chains had the gt conformation. This idea already existed because of elastic moduli calculations and 13C-solid state NMR data. Recently, the structure of cellotetraose was determined. There appear to be a striking similarity between the structure obtained from the MD simulations and this cellotetraose structure in terms of packing of the two independent molecules, the hydrogen bonding network and the conformations of the hydroxymethyl group, which were also gt for both molecules. The structure forms a 3D hydrogen bonded network, and the contribution from electrostatics to the packing is more pronounced than in case of the Ibeta structure. In contrast to what is expected, in view of the irreversible transition of the cellulose I to II form, the energies of the Ibeta form is found to be lower than that of II by 1 kcal mol(-1) per cellobiose.

Carbohydrate Conformation↗
PubMed2004

Reversible scaling of dihedral angle barriers during molecular dynamics to improve structure prediction of cyclic peptides.

Peptide cyclization or chemical cross-linking has frequently been used to restrict the conformational freedom of a peptide, for example, to enhance its capacity for selective binding to a target receptor molecule. Structure prediction of cyclic peptides is important to evaluate possible conformations prior to synthesis. Because of the conformational constraints imposed by cyclization low energy conformations of cyclic peptides can be separated by large energy barriers. In order to improve the conformational search properties of molecular dynamics (MD) simulations a potential scaling method has been designed. The approach consists of several consecutive MD simulations with a specific lowering of dihedral energy barriers and reduced nonbonded interactions between atoms separated by three atoms followed by gradually scaling the potential until the original barriers are reached. Application to four cyclic penta- and hexa-peptide test cases and a protein loop of known structure indicates that the potential scaling method is more efficient and faster in locating low energy conformations than standard MD simulations. Combined with a generalized Born implicit solvation model the low energy cyclic peptide conformations and the loop structure are in good agreement with experiment. Applications in the presence of explicit water molecules during the simulations showed also improved convergence to structures close to experiment compared with regular MD.

Amino Acid Sequence↗
PubMed2005

CD4 binding partially locks the bridging sheet in gp120 but leaves the beta2/3 strands flexible.

The structure of the free form HIV gp120, critical for therapeutic agent development, is unavailable due to its high flexibility. Previous thermodynamic data, structural analysis and simulation results have suggested a large conformational change in the core domain upon CD4 binding. The bridging sheet, which consists of four beta-strands with beta20/21 nestling against the inner/outer domains and beta2/3 facing outward, more exposed to the solvent, was proposed to be unfolded in the native state. In order to test this proposition and to characterize the native conformations, we performed potential mean force (PMF) molecular dynamics (MD) simulations on the CD4-bound crystal structure. We pushed the bridging sheet away from the inner and outer domain to explore the accessible conformational space for the bridging sheet. In addition, we performed conventional MD simulations on structures with the bridging sheet partially unfolded to investigate the stability of the association between the inner and outer domains. Based on the free energy profiles, we find that the whole bridging sheet is unlikely to unfold without other concurrent conformational changes. On the other hand, the partial bridging sheet, beta strands 2/3, can switch its conformation from the folded to the unfolded state. Furthermore, relaxation of conformation with partially unfolded bridging sheet through MD simulations leads to a conformation with beta strands 20/21 quickly re-anchoring against the inner and outer domains. Such a conformation, although lacking some of the hydrophobic interactions present in the CD4-bound structure, displayed high stability as further indicated by other restrained MD simulations. The relevance of this conformation to the free form structure and the pathway for conformational change from the free form to the CD4-bound structure is discussed in detail in light of the available unliganded SIV gp120 crystal structure.

Amino Acid Motifs↗
PubMed2003

Molecular dynamics simulations of a mixed DOPC/DOPG bilayer.

We have constructed a mixed dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol bilayer (DOPG) bilayer utilizing MD simulations. The aim was to develop an explicit molecular model of biological membranes as a complementary technique to neutron diffraction studies that are well established within the group. A monolayer was constructed by taking a previously customized PDB file of each molecule and arranging them in a seven rows of ten molecules and duplicated and rotated to form a bilayer. The 140-molecule bilayer contained 98 DOPC molecules and 42 DOPG molecules, in a 7:3 ratio in favour of DOPC. Sodium counter ions were placed near the phosphate moiety of DOPG to counteract the negative charge of DOPG. This was representative of the lipid ratio in a sample used for neutron diffraction. The MD package GROMACS was used for confining the bilayer in a triclinic box, adding Simple Polar Charge water molecules, energy minimization (EM). The bilayer/solvent system was subjected to EM using the steepest descent method to nullify bad contacts and reduce the potential energy of the system. Subsequent MD simulation using an initial NVT (constant number of particles, volume and temperature) for a 20 ps MD run followed by a NPT (constant number of particles, pressure and temperature) was performed. Structural parameters including volume of lipid, area of lipid, order parameter of the fatty acyl carbons and electron density profiles generated by the MD simulation were verified with values obtained from experimental data of DOPC, as there are no comparable experimental data available for the mixed bilayer.

Electrons↗
PubMed1999

Structure, dynamics and hydration of the nogalamycin-d(ATGCAT)2Complex determined by NMR and molecular dynamics simulations in solution.

The structure of the 1:1 nogalamycin:d(ATGCAT)2 complex has been determined in solution from high-resolution NMR data and restrained molecular dynamics (rMD) simulations using an explicit solvation model. The antibiotic intercalates at the 5'-TpG step with the nogalose lying along the minor groove towards the centre of the duplex. Many drug-DNA nuclear Overhauser enhancements (NOEs) in the minor groove are indicative of hydrophobic interactions over the TGCA sequence. Steric occlusion prevents a second nogalamycin molecule from binding at the symmetry-related 5'-CpA site, leading to the conclusion that the observed binding orientation in this complex is the preferred orientation free of the complication of end-effects (drug molecules occupy terminal intercalation sites in all X-ray structures) or steric interactions between drug molecules (other NMR structures have two drug molecules bound in close proximity), as previously suggested. Fluctuations in key structural parameters such as rise, helical twist, slide, shift, buckle and sugar pucker have been examined from an analysis of the final 500 ps of a 1 ns rMD simulation, and reveal that many sequence-dependent structural features previously identified by comparison of different X-ray structures lie within the range of dynamic fluctuations observed in the MD simulations. Water density calculations on MD simulation data reveal a time-averaged pattern of hydration in both the major and minor groove, in good agreement with the extensive hydration observed in two related X-ray structures in which nogalamycin is bound at terminal 5'-TpG sites. However, the pattern of hydration determined from the sign and magnitude of NOE and ROE cross-peaks to water identified in 2D NOESY and ROESY experiments identifies only a few "bound" water molecules with long residence times. These solvate the charged bicycloaminoglucose sugar ring, suggesting an important role for water molecules in mediating drug-DNA electrostatic interactions within the major groove. The high density of water molecules found in the minor groove in X-ray structures and MD simulations is found to be associated with only weakly bound solvent in solution.

Base Sequence↗
PubMedDate not supplied

Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes.

The enhanced permeability and retention of liposomes in solid tumors makes liposomal formulations attractive for the targeting of various antitumor agents. This study explores the binding, orientation, and dynamic properties of a potent topoisomerase I inhibitor, 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67), and its 20(S)-4-aminobutyrate ester prodrug (DB-67-AB) in DMPC liposomes by molecular dynamics (MD) simulations and experimental studies. MD simulations of an all-atom and fully hydrated liquid-crystalline bilayer (2 x 36 DMPC lipids) containing single molecules of DB-67 and DB-67-AB were conducted for up to 50 ns. Membrane/water partition coefficients for DB-67 and DB-67-AB vs pH were determined by ultracentrifugation. Fluorescence spectra and/or steady-state anisotropies were measured in various solvents and in DMPC liposomes. Kinetics for the reversible DB-67 lactone ring-opening in the presence and absence of DMPC liposomes were determined by HPLC with fluorescence detection. During the entire simulation time both DB-67 and DB-67-AB were located on the bilayer membrane near the polar ester groups of DMPC. The average depth of penetration for DB-67 and DB-67-AB was similar (12.4-13.2 A) with the prodrug's protonated amino group strongly solvated by surface water and lipid phosphate groups. Binding and fluorescence experiments revealed only a modest reduction in the binding affinity upon attachment of the ionized 4-aminobutyrate group onto DB-67. The binding microenvironment polarity resembles that of a polar solvent such as EtOH and DMSO. Kinetics experiments confirmed that DB-67 lactone hydrolysis is inhibited in the presence of DMPC liposomes, consistent with the reduced exposure of its lactone ring to water, as observed in the simulations. Both bound DB-67 and bound DB-67-AB have nonrandom orientations and reduced mobility in the membrane, especially for diffusion normal to the bilayer surface, and rotational relaxation, both of which are > or =2 orders of magnitude slower than in bulk water. MD simulations correctly predicted the high binding affinities for DB-67-AB to DMPC bilayers, protection of bound DB-67 toward lactone hydrolysis, and the lack of a substantial reduction in binding for the 20(S)-4-aminobutyrate prodrug of DB-67.

Antineoplastic Agents↗
PubMed1997

Structure and dynamic properties of diunsaturated 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine lipid bilayer from molecular dynamics simulation.

Unsaturated fatty acid chains are known to be an essential structural part of biomembranes, but only monounsaturated chains have been included in the molecular dynamics (MD) simulations of membrane systems. Here we present a 1-ns MD simulation for a diunsaturated 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (PLPC; 16:0/18:2[delta9,12]) bilayer. The structural behavior of the phosphatidylcholine headgroup, the glycerol backbone, and the hydrating water were assessed and found to be consistent with the existing information about similar systems from both experimental and computational studies. Further analysis was focused on the structure of the double bond region and the effects of the diunsaturation on the bilayer interior. The behavior of the diunsaturated sn-2 chains is affected by the tilted beginning of the chain and the four main conformations of the double bond region. The double bonds of the sn-2 chains also influenced the characteristics of the saturated chains in the sn-1 position. Furthermore, extreme conformations of the sn-2 chains existed that are likely to be related to the functional role of the double bonds. The results here point out the importance of polyunsaturation for the biological interpretations deduced from the membrane MD simulations.

Biophysical Phenomena↗
PubMed2002

Modeling the lipid component of membranes.

During the past several years, there have been a number of advances in the computational and theoretical modeling of lipid bilayer structural and dynamical properties. Molecular dynamics (MD) simulations have increased in length and time scales by about an order of magnitude. MD simulations continue to be applied to more complex systems, including mixed bilayers and bilayer self-assembly. A critical problem is bridging the gap between the still very small MD simulations and the time and length scales of experimental observations. Several new and promising techniques, which use atomic-level correlation and response functions from simulations as input to coarse-grained modeling, are being pursued.

Cell Membrane↗
PubMed2000

Dynamics of proteins predicted by molecular dynamics simulations and analytical approaches: application to alpha-amylase inhibitor.

The dynamics of alpha-amylase inhibitors has been investigated using molecular dynamics (MD) simulations and two analytical approaches, the Gaussian network model (GNM) and anisotropic network model (ANM). MD simulations use a full atomic approach with empirical force fields, while the analytical approaches are based on a coarse-grained single-site-per-residue model with a single-parameter harmonic potential between sufficiently close (r </= 7 A) residue pairs. The major difference between the GNM and the ANM is that no directional preferences can be obtained in the GNM, all residue fluctuations being theoretically isotropic, while ANM does incorporate directional preferences. The dominant modes of motions are identified by (i) the singular value decomposition (SVD) of the MD trajectory matrices, and (ii) the similarity transformation of the Kirchhoff matrices of inter-residue contacts in the GNM or ANM. The mean-square fluctuations of individual residues and the cross-correlations between domain movements retain the same characteristics, in all approaches-although the dispersion of modes and detailed amplitudes of motion obtained in the ANM conform more closely with MD results. The major weakness of the analytical approaches appears, on the other hand, to be their inadequacy to account for the anharmonic motions or multimeric transitions driven by the slowest collective mode observed in MD. Such motions usually suffer, however, from MD sampling inefficiencies, and multiple independent runs should be tested before making conclusions about their validity and detailed mechanisms. Overall this study invites attention to (i) the robustness of the average properties (mean-square fluctuations, cross-correlations) controlled by the low frequency motions, which are invariably reproduced in all approaches, and (ii) the utility and efficiency of the ANM, the computational time cost of which is of the order of "minutes" (real time), as opposed to "days" for MD simulations. Proteins 2000;40:512-524.

Computer Simulation↗
PubMed2001

Molecular dynamics simulation of class 3 aldehyde dehydrogenase.

Molecular dynamics (MD) simulation of the rat class 3 aldehyde dehydrogenase (ALDH) with nicotinamide dinucleotide (NAD) cofactors and explicit water molecules are reported. Our results demonstrate that MD simulation using the latest methodologies can maintain the crystal structure of the enzyme, as well as closely reproduce the short timescale dynamics of the enzyme. Furthermore, the examination of the distance between the nucleophilic Cys-243 and the NAD cofactor reveal important fluctuations that could be linked to ALDH catalysis. Finally, our quantum mechanical model of benzaldehyde in the active site of ALDH demonstrates that the enzyme requires only minor conformational changes to be poised for nucleophilic attack on the substrate.

Aldehyde Dehydrogenase↗
PubMed2005

Molecular dynamics simulations of helix-forming, amine-functionalized m-poly(phenyleneethynylene)s.

We present here the results of all-atom and united-atom molecular dynamics (MD) simulations that were used to examine the folding behavior of an amine-functionalized m-poly(phenyleneethynylene) (m-PPE) oligomer in aqueous environment. The parallelized GROMACS MD simulation code and OPLS force field were used for multiple MD simulations of m-PPE oligomers containing 24 phenyl rings in extended, coiled and helix conformations separately in water to determine the minimum energy conformation of the oligomer in aqueous solvent and what interactions are most important in determining this structure. Simulation results showed that the helix is the preferred minimum energy conformation of a single oligomer in water and that Lennard-Jones interactions are the dominant forces for the stabilization of the helix. In addition, these solvophobic interactions are strong enough to maintain the helix conformation at temperatures up to 523 K.

Alkynes↗
PubMed2001

Dynamics of internal water in fatty acid binding protein: computer simulations and comparison with experiments.

Multiple molecular dynamics (MD) simulations of fully solvated rat intestinal fatty acid binding protein (I-FABP) were conducted to investigate the dynamics of internal water molecules. Although the long time average of the number of internal water molecules in I-FABP is 22 as shown by the X-ray crystal structure, MD simulations predict large variations in the instantaneous number of internal water molecules on the nanosecond time scale. The computational model employed predicts that w135 (internal) and w217 (located on the protein surface) may be the water molecules with long residence times observed in previously reported magnetic relaxation dispersion studies. The average residence time of approximately 20 internal water molecules occupying the fatty acid binding cavity is estimated to be between 0.6 and 2.0 nanoseconds. Exchange of internal water in I-FABP appears to occur almost exclusively through the interface of beta-strands EF with the rest of the protein, which has significant implications for the pathways of the fatty acid entry and exit from the binding cavity. Proteins 2001;43:65-72.

Animals↗
PubMed2005

Distribution and effect of water content on molecular mobility in poly(vinylpyrrolidone) glasses: a molecular dynamics simulation.

PURPOSE: This work explores the distribution of water and its effects on molecular mobilities in poly(vinylpyrrolidone) (PVP) glasses using molecular dynamics (MD) simulation technology. METHODS: PVP glasses containing 0.5% and 10% w/w water and a small amount of ammonia and Phe-Asn-Gly were generated. Physical aging processes and associated structural and dynamic properties were monitored vs. time for periods up to 0.1 micros by MD simulation. RESULTS: Increasing water content from 0.5% to 10% w/w was found to reduce the Tg by about 90 K and increase the rates of volume and enthalpy relaxation. At 0.5% w/w, water molecules are mostly isolated and uniformly distributed while at 10% w/w, water distribution is markedly heterogeneous, with strands of water molecules occupying channels between the polymer chains. At 10% w/w, each water molecule has an average of 2.0 neighboring water molecules. The plasticization effects of water were revealed in diffusion coefficient increases of 3.7-, 7.3-, and 7.6-fold for water, ammonia, and the individual polyvinylpyrrolidone segments, respectively, and in shorter relaxation times (37- to 47-fold) for rotation of polymer segments with an elevation in water content from 0.5% to 10% w/w. Water diffusivity was found to linearly correlate with the number of neighboring water molecules. Rotation of the PVP segments is comprised of a fast wobble motion within a highly restrained cavity and a slow rotation over a wider angular space. Only the slow rotation was shown to be significantly affected by water content. CONCLUSIONS: Water distribution in the PVP glass is highly heterogeneous at 10% w/w water, reflecting the formation of water strands or small clusters rather than complete phase separation. Local enhancement of mobility with increasing water content has been demonstrated using MD simulations.

Algorithms↗
PubMed2005

Mechanical properties of surfactant bilayer membranes from atomistic and coarse-grained molecular dynamics simulations.

We use simulations to predict the stability and mechanical properties of two amphiphilic bilayer membranes. We carry out atomistic MD simulations and investigate whether it is possible to use an existing coarse-grained (CG) surfactant model to map the membrane properties. We find that certain membranes can be represented well by the CG model, whereas others cannot. Atomistic MD simulations of the erucate membrane yield a headgroup area per surfactant a(0) of 0.26 nm(2), an elastic modulus K(A) of 1.7 N/m, and a bending rigidity kappa of 5 k(B)T. We find that the CG model, with the right choice for the size and potential well depth of the head, correctly reproduces a(0), kappa, as well as the fluctuation spectrum over the whole range of q values. Atomistic MD simulations of EHAC, on the other hand, suggest that this membrane is unstable. This is indicated by the fact that kappa is of the order of k(B)T, which means that the interface is extremely flexible and diffuse, and K(A) is close to zero, which means that the surface tension is zero. We argue that the CG model can be used if the headgroups are uncharged, dipolar, or effectively dipolar due to headgroup charge screening induced by counterion condensation.

Journal Article↗
PubMed2001

Molecular dynamics simulation of adrenocorticotropin (1-10) peptide in a solvated dodecylphosphocholine micelle.

Adrenocorticotropin (ACTH) (1-10), an adrenocorticotropin hormone fragment, has been studied by molecular dynamics (MD) simulation in an NPT ensemble in an explicit dodecylphosphocholine (DPC) micelle. Two starting configurations of the peptide/micelle system, corresponding to the insertion and surface-binding modes, were used. A common equilibrated configuration, in which the peptide lies parallel to the micellar surface, was reached from both simulations. In the initial part of the simulations, distance restraints derived from NMR nuclear Overhauser enhancements were incorporated before the peptide reached an equilibrium configuration with respect to the micelle. Analyses of the trajectories from the subsequent free (unrestrained) MD simulation showed that ACTH (1-10) does not conform strictly to a helical structure. The loss of the helical structure is due to decreased intramolecular hydrogen bonding accompanied by an increase of hydrogen bonding between the amide protons of the peptide and the micellar head groups. However, the extent of the latter interaction is less pronounced than in the negatively charged SDS micelle. The final structure enhances the amphipathic nature of the peptide, facilitating better interactions at the water-hydrophobic interface. The primary hydrophobic interactions with the micelle came from the side chains of Met4, Phe7, and Trp9. All peptide bonds were either hydrated or were involved in intramolecular hydrogen bonding. The interactions with the DPC micelle, the conformation of the bound peptide, and the dynamics of the peptide, as revealed by the time correlation functions of the N-H bonds, were compared with those of the ACTH (1-10)/SDS system studied previously by MD simulations.

Adrenocorticotropic Hormone↗
PubMed2004

Anomalous mixing behavior of polyisobutylene/polypropylene blends: molecular dynamics simulation study.

The unusual mixing behavior of polyisobutylene (PIB) with head-to-head (hhPP) and head-to-tail polypropylene (PP) is studied using large-scale molecular dynamics (MD). The heats of mixing and Flory chi parameters were computed from MD simulations of both blends using a united atom model. The chi parameters from the simulations were estimated from the structure factors using the random phase approximation in analogy with neutron scattering (SANS) experiments. MD simulations for syndiotactic hhPP/PIB predicted a lower critical solution temperature with a chi parameter in very good agreement with SANS experiments on the atactic hhPP/PIB blend. MD simulations also predicted that the isotactic PP/PIB blend was immiscible at high molecular weight in qualitative agreement with cloud point measurements on atactic PP/PIB.

Journal Article↗
PubMed2002

Molecular dynamics simulations as a tool for improving protein stability.

Haloalkane dehalogenase (DhlA) was used as a model protein to explore the possibility to use molecular dynamics (MD) simulations as a tool to identify flexible regions in proteins that can serve as a target for stability enhancement by introduction of a disulfide bond. DhlA consists of two domains: an alpha/beta-hydrolase fold main domain and a cap domain composed of five alpha-helices. MD simulations of DhlA showed high mobility in a helix-loop-helix region in the cap domain, involving residues 184-211. A disulfide cross-link was engineered between residue 201 of this flexible region and residue 16 of the main domain. The mutant enzyme showed substantial changes in both thermal and urea denaturation. The oxidized form of the mutant enzyme showed an increase of the apparent transition temperature from 47.5 to 52.5 degrees C, whereas the T(m,app) of the reduced mutant decreased by more than 8 degrees C compared to the wild-type enzyme. Urea denaturation results showed a similar trend. Measurement of the kinetic stability showed that the introduction of the disulfide bond caused a decrease in activation free energy of unfolding of 0.43 kcal mol(-1) compared to the wild-type enzyme and also indicated that the helix-loop-helix region was involved early in the unfolding process. The results show that MD simulations are capable of identifying mobile protein domains that can successfully be used as a target for stability enhancement by the introduction of a disulfide cross-link.

Computer Simulation↗
PubMed2005

Effective force field for liquid hydrogen fluoride from ab initio molecular dynamics simulation using the force-matching method.

A recently developed force-matching method for obtaining effective force fields for condensed matter systems from ab initio molecular dynamics (MD) simulations has been applied to fit a simple nonpolarizable two-site pairwise force field for liquid hydrogen fluoride. The ab initio MD in this case was a Car-Parrinello (CP) MD simulation of 64 HF molecules at nearly ambient conditions within the Becke-Lee-Yang-Parr approximation to the electronic density functional theory. The force-matching procedure included a fit of short-ranged nonbonded forces, bonded forces, and atomic partial charges. The performance of the force-match potential was examined for the gas-phase dimer and for the liquid phase at various temperatures. The model was able to reproduce correctly the bent structure and energetics of the gas-phase dimer, while the results for the structural properties, self-diffusion, vibrational spectra, density, and thermodynamic properties of liquid HF were compared to both experiment and the CP MD simulation. The force-matching model performs well in reproducing nearly all of the liquid properties as well as the aggregation behavior at different temperatures. The model is computationally cheap and compares favorably to many more computationally expensive potential energy functions for liquid HF.

Chemistry, Physical↗