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PubMed2006

Structural changes and binding characteristics of the tetracycline-repressor binding site on induction.

The binding motif (pharmacophore) for induction and the changes in the structure of the binding site that accompany induction have been determined from molecular-dynamics simulations on the tetracycline-repressor signal-transduction protein. The changes and the induction mechanism are discussed and compared with conclusions drawn from earlier X-ray structures. The differences in inducer strength of tetracycline and 5a,6-anhydrotetracycline are discussed with respect to their interaction in the MD simulations.

Allosteric Regulation↗
PubMed2006

Energy loss of a charged particle moving over a 2D strongly coupled dusty plasma.

We use molecular dynamics (MD) simulation to evaluate the energy loss of a charged projectile moving parallel to a two-dimensional strongly coupled dusty plasma and compare the results with those obtained from the quasilocalized charge approximation (QLCA) and the Vlasov-random phase approximation. Good agreement is found between the QLCA and MD results when the projectile-dust coupling is weak. In the opposite regime, nonlinear effects in the dust-layer response render the QLCA model increasingly inadequate for calculating the energy losses at low projectile speeds.

Journal Article↗
PubMed2004

Superlubricity: a paradox about confined fluids resolved.

Using the method of Frantz and Salmeron to cleave mica [Tribol. Lett. 5, 151 (1998)]] we investigate alkane fluids in a surface forces apparatus and confirm several predictions of molecular dynamics (MD) simulation. An oscillatory force-distance profile is observed for the methyl-branched alkane, squalane. Boundary slip is inferred from the frictional sliding of molecularly thin fluids and also from the hydrodynamic flow of thicker films. These findings resolve the paradox that prior experiments disagreed with these aspects of MD predictions, and demonstrate that exceptionally low energy dissipation is possible when fluids move past solid surfaces that are sufficiently smooth.

Journal Article↗
PubMed2000

The nicotinic acetylcholine receptor: from molecular model to single-channel conductance.

The nicotinic acetylcholine receptor (nAChR) is the archetypal ligand-gated ion channel. A model of the alpha7 homopentameric nAChR is described in which the pore-lining M2 helix bundle is treated atomistically and the remainder of the molecule is treated as a "low resolution" cylinder. The surface charge on the cylinder is derived from the distribution of charged amino acids in the amino acid sequence (excluding the M2 segments). This model is explored in terms of its predicted single-channel properties. Based on electrostatic potential profiles derived from the model, the one-dimensional Poisson-Nernst-Planck equation is used to calculate single-channel current/voltage curves. The predicted single-channel conductance is three times higher (ca. 150 pS) than that measured experimentally, and the predicted ion selectivity agrees with the observed cation selectivity of nAChR. Molecular dynamics (MD) simulations are used to estimate the self-diffusion coefficients (D) of water molecules within the channel. In the narrowest region of the pore, D is reduced ca. threefold relative to that of bulk water. Assuming that the diffusion of ions scales with that of water, this yields a revised prediction of the single-channel conductance (ca. 50 pS) in good agreement with the experimental value. We conclude that combining atomistic (MD) and continuum electrostatics calculations is a promising approach to bridging the gap between structure and physiology of ion channels.

Computer Simulation↗
PubMed2005

Self-diffusion and transport diffusion of light gases in metal-organic framework materials assessed using molecular dynamics simulations.

Metal-organic framework (MOF) materials pose an interesting alternative to more traditional nanoporous materials for a variety of separation processes. Separation processes involving nanoporous materials can be controlled by either adsorption equilibrium, diffusive transport rates, or a combination of these factors. Adsorption equilibrium has been studied for a variety of gases in MOFs, but almost nothing is currently known about molecular diffusion rates in MOFs. We have used equilibrium molecular dynamics (MD) to probe the self-diffusion and transport diffusion of a number of small gas species in several MOFs as a function of pore loading at room temperature. Specifically, we have studied Ar, CH4, CO2, N2, and H2 diffusion in MOF-5. The diffusion of Ar in MOF-2, MOF-3, and Cu-BTC has been assessed in a similar manner. Our results greatly expand the range of MOFs for which data describing molecular diffusion is available. We discuss the prospects for exploiting molecular transport properties in MOFs in practical separation processes and the future role of MD simulations in screening families of MOFs for these processes.

Journal Article↗
PubMed1999

Smoluchowski dynamics of the vnd/NK-2 homeodomain from Drosophila melanogaster: first-order mode-coupling approximation.

This work is the first in a series devoted to applying mode coupling diffusion theory to the derivation of local dynamics properties of proteins in solution. The first-order mode-coupling approximation, or optimized Rouse-Zimm local dynamics (ORZLD), is applied here to derive the rotational dynamics of the bonds and compare the calculated with the experimental nmr 15N spin-lattice relaxation time behavior of the vnd/NK-2 homeodomain from Drosophila melanogaster. The starting point for the calculations is the experimental three-dimensional structure of the homeodomain determined by multidimensional nmr spectroscopy. The results of the computations are compared with experimentally measured 15N spin-lattice relaxation times T1, at 34.5 and 60.8 MHz, to check the first-order approximation. To estimate the relative importance of internal and overall rotation, both rigid and fluctuating dynamic models are examined, with fluctuations evaluated using molecular dynamics (MD) simulations. The correlation times for the fundamental bond vector time correlation function and for the second-order bond orientational TCF are obtained as a function of the residue number for vnd/NK-2. The stability of the corresponding local dynamics pattern for the fluctuating structure as a function of the length of the MD trajectory is presented. Diffusive dynamics, which is essentially free of model parameters even at first order in the mode-coupling diffusion approach, confirm that local dynamics of proteins can be described in terms of rotational diffusion of a fluctuating quasi-rigid structure. The comparison with the nmr data shows that the first-order mode coupling diffusion approximation accounts for the correct order of magnitude of the results and of important qualitative aspects of the data sensitive to conformational changes. Indications are obtained from this study to efficiently extend the theory to higher order in the mode-coupling expansion. These results demonstrate the promise of the mode-coupling approach, where the local dynamics of proteins is described in terms of rotational diffusion of a fluctuating quasi-rigid structure, to analyze nmr spin-lattice relaxation behavior.

Animals↗
PubMed2002

Folded conformation of an immunostimulating tetrapeptide rigin: high temperature molecular dynamics simulation study.

Employing high temperature quenched molecular dynamics (QMD) stimulations the conformational energy space of an immunostimulating tetrapeptide rigin: H-Gly341-Gln-Pro-Arg344-OH, is explored. Using distance dependent dielectric (epsilon =r(ij)) 31 different low energy starting structures with identical sequence were computed for their conformational preferences. According to the hypothesis of O'Connors et al. [J. Med. Chem. 35 (1992), 2870], 83 low-energy conformers resulted from unrestrained molecular dynamics (MD) simulations, could be classified into two energy minimized families: A and B, comprised of 64 (Pro C(gamma)-endo orientation) and 19 (Pro C(gamma)-exo orientation) structures, respectively. An examination of these families revealed the existence of a remarkably similar folded backbone conformation: torsion angles being phi(i+1) approximately -65 degrees, psi(i+1) approximately -65 degrees, phi(i+2) approximately -65 degrees, psi(i+2) approximately -60 degrees, characterizing a distorted type III beta-turn structure across the central Gln-Pro segment. The folded conformation of rigin is devoid of a classical 1 <-- 4 intra-molecular hydrogen bond nevertheless, the conformation is stabilized by an effective 'salt-bridge', i.e., Gly H(3)N(+)...C(alpha)OO(-) Arg interaction. Surprisingly, in both the families the unusual folded side-chain dispositions of the Gln residue favor the formation of a unique intra-residue 'main-chain to side-chain' H-bond, i.e., N(alpha)-H...N(epsilon) interaction, encompassing a seven-membered ring motif. The conformational attributes may be valuable in de novo construction of structure-based drug candidates having sufficient stimulating activity.

Adjuvants, Immunologic↗
PubMed2003

Interplay between hydrophobic cluster and loop propensity in beta-hairpin formation: a mechanistic study.

We investigated the structural determinants of the stability of a designed beta-hairpin containing a natural hydrophobic cluster from the protein GB1 and a D-Pro-Gly turn forming sequence. The results of our simulations shed light on the factors leading to an ordered secondary structure in a model peptide: in particular, the importance of the so-called diagonal interactions in forming a stable hydrophobic nucleus in the beta-hairpin, together with the more obvious lateral interactions, is examined. With the use of long timescale MD simulations in explicit water, we show the role of diagonal interactions in driving the peptide to the correct folded structure (formation of the hydrophobic core with Trp 2, Tyr 4, and Phe 9 in the first stages of refolding) and in keeping it in the ensemble of folded conformations. The combination of the stabilizing effects of the D-Pro-Gly turn sequence and of the hydrophobic nucleus formation thus favors the attainment of an ordered secondary structure compatible with the one determined experimentally. Moreover, our data underline the importance of the juxtapositions of the side chains of amino acids not directly facing each other in the three-dimensional structure. The combination of these interactions forces the peptide to sample a nonrandom portion of the conformational space, as can be seen in the rapid collapse to an ordered structure in the refolding simulation, and shows that the unfolded state can be closely correlated to the folded ensemble of structures, at least in the case of small model peptides.

Computer Simulation↗
PubMed1995

Molecular dynamics simulations of excimer forming (+)-anti-BPDE-DNA adducts in aqueous solution.

The chemical carcinogen (+)-anti BPDE preferentially binds covalently to the guanine base in the minor groove of DNA. Fluorescence spectroscopic studies have shown that the BPDE molecules bound to DNA can interact in their photo-excited state giving strong excimer fluorescence when bound to poly(dGdC).poly(dGdC). It was suggested that the formation of such excited state complexes is most probable when the two (+)-anti-BPDE bind to guanines of adjacent base pairs on the two different strands of the DNA. In the present work a model for such an excimer forming DNA-BPDE double adduct system has been constructed and shown to be stable over a 300 ps molecular dynamics simulation in a water box. The model is a d(CG)3.d(CG)3 molecule with two BPDE molecules bound to the guanines at the 4th position on each strand, located in the minor groove and each oriented towards the 5' end of the modified strand, respectively. The results of 300 ps MD simulation show that the two BPDE chromophores exhibited on the average a relative geometry favourable for excimer formation. The local structure at the adduct position was considerably distorted and the helix axis was bent. The modified bases were found to be paired through a stable single non-Watson Crick type of hydrogen bond.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2002

Molecular dynamics study of peptides in implicit water: ab initio folding of beta-hairpin, beta-sheet, and beta beta alpha-motif.

In this communication, we have demonstrated that molecular dynamics simulations using a GB implicit solvation model with the all-atom based force field (CHARMM19) can describe the spontaneous folding of small peptides in aqueous solution. The native structures of peptides with various structural motifs (beta-hairpin, beta-sheet, and betabetaalpha-moiety) were successfully predicted within reasonable time scales by MD simulations at moderately elevated temperatures. It is expected that the present simulations provide further insight into mechanism/pathways of the peptide folding.

Amino Acid Sequence↗
PubMed2004

On the stability of different experimental dimeric structures of the SL1 sequence from the genomic RNA of HIV-1 in solution: a molecular dynamics simulation and electrophoresis study.

SL1 is a stem-loop RNA sequence from the genome of HIV-1 thought to be the initiation site for the dimerization of the retroviral genomic RNA. The aim of this study is to check the stability in solution of different experimental dimeric structures available in the literature. Two kinds of dimer have been evidenced: an extended duplex looking like a double helix with two internal bulges and a kissing complex in which the monomers with a stem/loop conformation are linked by intermolecular loop-loop interactions. Two divergent experimental structures of the kissing complex from the Lai isolate are reported in the literature, one obtained from NMR (Mujeeb et al., Nature Structural Biology, 1998, Vol. 5, pp. 432-436) and the other one from x-ray crystallography (Ennifar et al., Nature Structural Biology, 2001, Vol. 8, pp. 1064-1068). A crystallographic structure of the Mal isolate was also reported (Ennifar et al., Nature Structure Biology, 2001, Vol. 8, pp. 1064-1068). Concerning the extended duplex, a NMR structure is available for Lai (Girard et al., Journal of Biomolecular Structure and Dynamics, 1999, Vol. 16, pp. 1145-1157) and a crystallographic structure for Mal (Ennifar et al., Structure, 1999, Vol. 7, pp. 1439-1449). Using a molecular dynamics technique, all these experimental structures have been simulated in solution with explicit water and counterions. We show that both extended duplex structures are stable. On the contrary, the crystallographic structures of the Lai and Mal kissing complexes are rapidly destabilized in aqueous environment. Finally, the NMR structure of the Lai loop-loop kissing complex remains globally stable over a 20 ns MD simulation, although large rearrangements occur at the level of the stem/loop junctions that are flexible, as shown from free energy calculations. These results are compared to electrophoresis experiments on dimer formation.

Computer Simulation↗
PubMed2005

Cytochrome P450cam-monoterpene interactions.

The use of the molecular mechanics AMBER force field (FF) to predict product profiles for the hydroxylation of the monoterpenes 1R-camphor, 1S-camphor, 1R-norcamphor, 1S-norcamphor and camphane by the enzyme cytochrome P450cam from the soil bacterium Pseudomonas putida was investigated. Predictions were carried out by applying multiple substrate (starting) orientations in the enzyme pocket in two procedures: a procedure based on molecular dynamics (MD) and a procedure based on short MD simulations followed by geometry optimisations. The latter (GO) procedure is faster and enabled the use of more monoterpene starting orientations. Monoterpene orientations were transformed into product profiles by applying both energetic and geometrical criteria appropriate for the (monoterpene) hydrogen abstraction reaction. Good predictions compared to experimental data were obtained for most compounds in both the MD and GO procedures. Prior to the product profile calculations, the FF was calibrated by reproducing the experimental data for the binding energy of 1R-camphor and 1S-camphor to P450cam and the energy of vaporisation of water. Focus of the calibration was on the value for the scaling factor for the electrostatic interactions.

Camphor↗
PubMed1999

A molecular dynamics study of the 41-56 beta-hairpin from B1 domain of protein G.

The structural and dynamical behavior of the 41-56 beta-hairpin from the protein G B1 domain (GB1) has been studied at different temperatures using molecular dynamics (MD) simulations in an aqueous environment. The purpose of these simulations is to establish the stability of this hairpin in view of its possible role as a nucleation site for protein folding. The conformation of the peptide in the crystallographic structure of the protein GB1 (native conformation) was lost in all simulations. The new equilibrium conformations are stable for several nanoseconds at 300K (>10 ns), 350 K (>6.5 ns), and even at 450 K (up to 2.5 ns). The new structures have very similar hairpin-like conformations with properties in agreement with available experimental nuclear Overhauser effect (NOE) data. The stability of the structure in the hydrophobic core region during the simulations is consistent with the experimental data and provides further evidence for the role played by hydrophobic interactions in hairpin structures. Essential dynamics analysis shows that the dynamics of the peptide at different temperatures spans basically the same essential subspace. The main equilibrium motions in this subspace involve large fluctuations of the residues in the turn and ends regions. Of the six interchain hydrogen bonds, the inner four remain stable during the simulations. The space spanned by the first two eigenvectors, as sampled at 450 K, includes almost all of the 47 different hairpin structures found in the database. Finally, analysis of the hydration of the 300 K average conformations shows that the hydration sites observed in the native conformation are still well hydrated in the equilibrium MD ensemble.

Amino Acid Sequence↗
PubMed2000

Analysis of inelastic x-ray scattering spectra of low-temperature water

We analyze a set of high-resolution inelastic x-ray scattering (IXS) spectra from H2O measured at T=259, 273, and 294 K using two different phenomenological models. Model I, called the "dynamic cage model," combines the short time in-cage dynamics described by a generalized Enskog kinetic theory with a long-time cage relaxation dynamics described by an alpha relaxation. This model is appropriate for supercooled water where the cage effect is dominant and the existence of an alpha relaxation is evident from molecular-dynamics (MD) simulation data of extended simple point charge (SPC/E) model water. Model II is essentially a generalized hydrodynamic theory called the "three effective eigenmode theory" by de Schepper et al. 11. This model is appropriate for normal liquid water where the cage effect is less prominent and there is no evidence of the alpha relaxation from the MD data. We use the model I to analyze IXS data at T=259 K (supercooled water). We successfully extract the Debye-Waller factor, the cage relaxation time from the long-time dynamics, and the dispersion relation of high-frequency sound from the short time dynamics. We then use the model II to analyze IXS data at all three temperatures, from which we are able to extract the relaxation rate of the central mode and the damping of the sound mode as well as the dispersion relation for the high-frequency sound. It turns out that the dispersion relations extracted from the two models at their respective temperatures agree with each other giving the high-frequency sound speed of 2900+/-300 m/s. This is to be compared with a slightly higher value reported previously, 3200+/-320 m/s, by analyzing similar IXS data with a phenomenological-damped harmonic oscillator model 22. This latter model has traditionally been used exclusively for the analysis of inelastic scattering spectra of water. The k-dependent sound damping and central mode relaxation rate extracted from our model analyses are compared with the known values in the hydrodynamic limit.

Journal Article↗
PubMed2005

pH-dependent conformational flexibility of the SARS-CoV main proteinase (M(pro)) dimer: molecular dynamics simulations and multiple X-ray structure analyses.

The SARS coronavirus main proteinase (M(pro)) is a key enzyme in the processing of the viral polyproteins and thus an attractive target for the discovery of drugs directed against SARS. The enzyme has been shown by X-ray crystallography to undergo significant pH-dependent conformational changes. Here, we assess the conformational flexibility of the M(pro) by analysis of multiple crystal structures (including two new crystal forms) and by molecular dynamics (MD) calculations. The MD simulations take into account the different protonation states of two histidine residues in the substrate-binding site and explain the pH-activity profile of the enzyme. The low enzymatic activity of the M(pro) monomer and the need for dimerization are also discussed.

Binding Sites↗
PubMed1996

On simulating lipid bilayers with an applied surface tension: periodic boundary conditions and undulations.

As sketched in Fig. 1, a current molecular dynamics computer simulation of a lipid bilayer fails to capture significant features of the macroscopic system, including long wavelength undulations. Such fluctuations are intrinsically connected to the value of the macroscopic (or thermodynamic) surface tension (cf. Eqs. 1 and 9; for a related treatment, see Brochard et al., 1975, 1976). Consequently, the surface tension that might be evaluated in an MD simulation should not be expected to equal the surface tension obtained from macroscopic measurements. Put another way, the largest of the three simulations presented here contained over 16,000 atoms and required substantial computer time to complete, but modeled a system of only 36 lipids per side. From this perspective it is not surprising that the system is not at the thermodynamic limit. An important practical consequence of this effect is that simulations with fluctuating area should be carried out with a nonzero applied surface tension (gamma 0 of Fig. 2) even when the macroscopic tension is zero, or close to zero. Computer simulations at fixed surface area, which can explicitly determine pressure anisotropy at the molecular level, should ultimately lend insight into the value of gamma 0, including its dependence on lipid composition and other membrane components. As we have noted and will describe further in separate publications (Feller et al., 1996; Feller et al., manuscript in preparation), surface tensions obtained from simulations can be distorted by inadequate initial conditions and convergence, and are sensitive to potential energy functions, force truncation methods, and system size; it is not difficult, in fact, to tune terms in the potential energy function so as to yield surface tensions close to zero. This is why parameters should be tested extensively on simpler systems, for example, monolayers. The estimates of gamma 0 that we have presented here should be regarded as qualitative, and primarily underscore the assertion that the surface tension of a microscopically flat, simulation-sized patch is significantly greater than zero. As the simulation cell length increases, the surface tension that would be evaluated (or should be applied) decreases; in the limit of micrometer-sized simulation cells, gamma would approach zero or its appropriate thermodynamic value. The theories presented here also imply that the estimation of bilayer surface tension from monolayer data should take the degree of flatness into account. These conclusions are independent of the precise values of parameters such as bending constants. In conclusion, from the simulator's perspective, the question "What is the surface tension of a bilayer?" is better phrased as "What is the value of the applied surface tension necessary to simulate a particular experimental system with a given number of lipids?". As we have shown, the answer to the second question varies, but it should not be assumed a priori to equal zero.

Biophysical Phenomena↗
PubMed2005

Relating side-chain mobility in proteins to rotameric transitions: insights from molecular dynamics simulations and NMR.

The dynamic aspect of proteins is fundamental to understanding protein stability and function. One of the goals of NMR studies of side-chain dynamics in proteins is to relate spin relaxation rates to discrete conformational states and the timescales of interconversion between those states. Reported here is a physical analysis of side-chain dynamics that occur on a timescale commensurate with monitoring by 2H spin relaxation within methyl groups. Motivated by observations made from tens-of-nanoseconds long MD simulations on the small protein eglin c in explicit solvent, we propose a simple molecular mechanics-based model for the motions of side-chain methyl groups. By using a Boltzmann distribution within rotamers, and by considering the transitions between different rotamer states, the model semi-quantitatively correlates the population of rotamer states with 'model-free' order parameters typically fitted from NMR relaxation experiments. Two easy-to-use, analytical expressions are given for converting S2 (axis') values (order parameter for C-CH3 bond) into side-chain rotamer populations. These predict that S2 (axis') values below 0.8 result from population of more than one rotameric state. The relations are shown to predict rotameric sampling with reasonable accuracy on the ps-ns timescale for eglin c and are validated for longer timescales on ubiquitin, for which side-chain residual dipolar coupling (RDC) data have been collected.

Carbon↗
PubMed2005

Structure and energy landscape of a photoswitchable peptide: a replica exchange molecular dynamics study.

A replica exchange molecular dynamics (REMD) simulation of a bicyclic azobenzene peptide in explicit dimethyl sulfoxide solution is presented in order to characterize the conformational structures and energy landscape of a photoswitchable peptide. It is shown that an enhanced-sampling technique such as the REMD method is essential to obtain a converged conformational sampling of the peptide at room temperature. This is because conventional MD simulations of less than approximately 100-ns length are either trapped in local minima (at 295 K) or-if run at high temperature-do not resemble the room-temperature REMD results. Calculating various nuclear Overhauser effects (NOEs) and (3)J-couplings, a good overall agreement between the REMD simulations and the NMR experiments of Renner et al. (Biopolymers 2000;54:501-514) is found. In particular, the REMD study confirms the general picture drawn by Renner et al. that the trans-isomer of the azobenzene peptide exhibits a well-defined structure, while the cis-isomer is a conformational heterogeneous system; that is, the trans-isomer occurs in 2 well-defined conformers, while the cis-isomer represents an energetically frustrated system that leads to an ensemble of conformational structures. Employing a principal component analysis of the REMD data, the free energy landscape of the systems is studied at various temperatures. The implications for the folding and unfolding pathways of the system are discussed.

Algorithms↗