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PubMed1992

Quenched molecular dynamics simulations of tuftsin and proposed cyclic analogues.

We have used high-temperature quenched molecular dynamics calculations to investigate the conformational properties of tuftsin (Thr-Lys-Pro-Arg) in solution. Conformers obtained after quenching of the dynamical structures were sorted into families depending on their relative energies and backbone conformations. By examination of these families, several cyclic analogues of tuftsin were proposed and examined theoretically by further quenched dynamics simulations. Two of the four proposed analogues were found to adopt essentially identical conformations to that of linear tuftsin. It is suggested that these two derivatives (cyclo[Thr-Lys-Pro-Arg-Gly] and cyclo[Thr-Lys-Pro-Arg-Asp]) may be biologically active, and that the introduction of cyclic conformational constraints should help to reduce the entropic penalty to peptide binding.

Amino Acid Sequence↗
PubMed2003

Molecular dynamics simulations of a protein model in uniform and elongational flows.

We present a molecular dynamics study of the conformational deformation of a minimalist beta-barrel protein model in two different types of hydrodynamic flows: uniform and elongational. We investigate the characteristics of protein stretching, paying special attention to the unfolding intermediate states and their relationship to the protein folding/unfolding problem. In the uniform flow simulations, one end of the modeled protein was tethered to a fixed point in space and the forced unfolding process was observed. The unfolding takes place via a few stages involving one or two intermediate states, depending on which end is tethered. The calculated force-extension curves show plateau regimes and hysteresis as the protein is stretched and refolded, in qualitative agreement with the experimental measurements. The physical behavior observed in our numerical simulations of the forced unfolding in an elongational flow is very different from that in uniform flow. The protein unfolds abruptly from the globular state to a fully stretched state without going through any observable intermediate states. From these observation, we stress that protein unfolding pathways under the influence of an external force are highly dependent on the mechanism of the exerted force.

Computer Simulation↗
PubMed2005

Electronic relaxation dynamics of Ni2+-ion aqueous solution: molecular-dynamics simulation.

Electronic relaxation dynamics of Ni2+-ion aqueous solution is investigated using molecular-dynamics (MD) simulations with the model-effective Hamiltonian developed previously. The nonadiabatic transition rates from the first three excited states to the ground state are evaluated by the golden rule formula with the adiabatic MD simulations. The MD simulations with the fewest-switch surface-hopping method are also carried out to obtain a more detailed description of the electronic relaxation dynamics among the excited states. We found out that the transitions among the three excited states are very fast, in the order of 10 fs, while the transition between the excited and ground states is slow, about 800 ps. These findings are consistent with the time scales of energy dissipation detected by the transient lens experiment. In both simulations, we explore the effects of the quantum decoherence, where the decoherence functions are derived by the energy-gap dynamics with the displaced harmonic-oscillator model.

Journal Article↗
PubMed2006

Collective dynamics of EcoRI-DNA complex by elastic network model and molecular dynamics simulations.

Anisotropic network model (ANM) is used to analyze the collective motions of restriction enzyme EcoRI in free form and in complex with DNA. For comparison, three independent molecular dynamics (MD) simulations, each of 1.5 ns duration, are also performed for the EcoRI-DNA complex in explicit water. Although high mobility (equilibrium fluctuations) of inner and outer loops that surround the DNA is consistent in both methods and experiments, MD runs sample different conformational subspaces from which reliable collective dynamics cannot be extracted. However, ANM employed on different conformations from MD simulations indicates very similar collective motions. The stems of the inner loops are quite immobile even in the free enzyme and form a large, almost fixed, pocket for DNA binding. As a result, the residues that make specific and non-specific interactions with the DNA exhibit very low fluctuations in the free enzyme. The vibrational entropy difference between the EcoRI complex and free protein + unkinked DNA is positive (favorable), which may partially counteract the unfavorable enthalpy difference of DNA kink formation. Dynamic domains in EcoRI complex and cross-correlations between residue fluctuations indicate possible means of communication between the distal active sites.

Computer Simulation↗
PubMed2001

Finite-size dependence of the bridge function extracted from molecular dynamics simulations.

The bridge function for liquid sodium at T=373 K is obtained by using the mean spherical approximation to extrapolate the pair distribution function (PDF), calculated in molecular dynamics (MD) simulations, beyond the half simulation box length for two sizes of the MD system. The bridge function is found to strongly depend on the total number of particles used in the simulation cell. This dependency leads to a spurious maximum of the static structure factor at long wavelengths, obtained from the reference hypernetted-chain approximation (RHNC) with the MD system used as a reference system (RHNC-MD). A simple self-consistent procedure, proposed to account for the finite-size effects in the bridge function, allows one to efficiently correct the RHNC-MD static structure factor for all unphysical manifestations.

Journal Article↗
PubMed2005

Molecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors.

Nuclear receptor (NR) ligands occupy a pocket that lies within the core of the NR ligand-binding domain (LBD), and most NR LBDs lack obvious entry/exit routes upon the protein surface. Thus, significant NR conformational rearrangements must accompany ligand binding and release. The precise nature of these processes, however, remains poorly understood. Here, we utilize locally enhanced sampling (LES) molecular dynamics computer simulations to predict molecular motions of x-ray structures of thyroid hormone receptor (TR) LBDs and determine events that permit ligand escape. We find that the natural ligand 3,5,3'-triiodo-L-thyronine (T(3)) dissociates from the TRalpha1 LBD along three competing pathways generated through i), opening of helix (H) 12; ii), separation of H8 and H11 and the Omega-loop between H2 and H3; and iii), opening of H2 and H3, and the intervening beta-strand. Similar pathways are involved in dissociation of T(3) and the TRbeta-selective ligand GC24 from TRbeta; the TR agonist IH5 from the alpha- and beta-TR forms; and Triac from two natural human TRbeta mutants, A317T and A234T, but are detected with different frequencies in simulations performed with the different structures. Path I was previously suggested to represent a major pathway for NR ligand dissociation. We propose here that Paths II and III are also likely ligand escape routes for TRs and other NRs. We also propose that different escape paths are preferred in different situations, implying that it will be possible to design NR ligands that only associate stably with their cognate receptors in specific cellular contexts.

Algorithms↗
PubMed2005

Effect of monovalent salt on cationic lipid membranes as revealed by molecular dynamics simulations.

An atomic-scale understanding of cationic lipid membranes is required for development of gene delivery agents based on cationic liposomes. To address this problem, we recently performed molecular dynamics (MD) simulations of mixed lipid membranes comprised of cationic dimyristoyltrimethylammonium propane (DMTAP) and zwitterionic dimyristoylphosphatidylcholine (DMPC) (Biophys. J. 2004, 86, 3461-3472). Given that salt ions are always present under physiological conditions, here we focus on the effects of monovalent salt (NaCl) on cationic (DMPC/DMTAP) membranes. Using atomistic MD simulations, we found that salt-induced changes in membranes depend strongly on their composition. When the DMTAP mole fraction is small (around 6%), the addition of monovalent salt leads to a considerable compression of the membrane and to a concurrent enhancement of the ordering of lipid acyl chains. That is accompanied by reorientation of phosphatidylcholine headgroups in the outward normal direction and slight changes in electrostatic properties. We attribute these changes to complexation of DMPC lipids with Na(+) ions which penetrate deep into the membrane and bind to the carbonyl region of the DMPC lipids. In contrast, at medium and high molar fractions of cationic DMTAP (50 and 75%) a substantial positive surface charge density of the membranes prevents the binding of Na(+) ions, making such membranes almost insensitive to monovalent salt. Finally, we compare our results to the Poisson-Boltzmann theory. With the exception of the immediate vicinity of the bilayer plane, we found excellent agreement with the theory. This is as expected since unlike in the theoretical description the surface is now structured due to its atomic scale nature.

Computer Simulation↗
PubMed1994

Molecular dynamics simulations of high-mannose oligosaccharides.

Conformations of several high-mannose-type oligosaccharides that are generated during the biosynthetic degradation of Man9GlcNAc2 to Man5GlcNAc2 have been studied by molecular dynamics (MD). Simulations were performed on NCI-FCRDC's Cray Y-MP 8D/8128 supercomputer using Biosym's CVFF force field for 1000 ps with different initial conformations. The conformations of the two alpha 1,3- and the two alpha 1,6-linkages in each oligomannose were different, suggesting that deriving oligosaccharide conformations based on the conformational preferences of the constituent disaccharide fragments will not always yield correct results. Unlike other oligomannoses, Man9GlcNAc2 appears to take more than one distinct conformation around the core alpha 1,6-linkage. These various conformations may play an important role in determining the processing pathways. Using the data on the preferred conformations of these oligomannoses and the available experimental results, possible pathways for processing Man9GlcNAc2 to Man5GlcNAc2 by alpha 1,2-linkage-specific mannosidases have been proposed. Conformational analysis of Man5GlcNAc2 indicates that the addition of beta 1,2-GlcNAc to the alpha 1,3-linked core mannose, besides serving as a prerequisite for mannosidase II action as suggested earlier, may also prevent the removal of alpha 1,3-mannose. The MD simulations also suggest that the processing of the precursor oligosaccharide during Asn-linked complex and hybrid glycan biosynthesis proceeds in a well-defined pathway involving more than one alpha 1,2-linkage-specific mannosidase. Knowledge of the conformation of the processing intermediates obtained from the present study can be used to design highly specific substrate analogues to inhibit a particular mannosidase, thereby blocking one processing pathway without interfering with the others.

Animals↗
PubMed2004

Beta-hairpin folding mechanism of a nine-residue peptide revealed from molecular dynamics simulations in explicit water.

The beta-hairpin fold mechanism of a nine-residue peptide, which is modified from the beta-hairpin of alpha-amylase inhibitor tendamistat (residues 15-23), is studied through direct folding simulations in explicit water at native folding conditions. Three 300-nanosecond self-guided molecular dynamics (SGMD) simulations have revealed a series of beta-hairpin folding events. During these simulations, the peptide folds repeatedly into a major cluster of beta-hairpin structures, which agree well with nuclear magnetic resonance experimental observations. This major cluster is found to have the minimum conformational free energy among all sampled conformations. This peptide also folds into many other beta-hairpin structures, which represent some local free energy minimum states. In the unfolded state, the N-terminal residues of the peptide, Tyr-1, Gln-2, and Asn-3, have a confined conformational distribution. This confinement makes beta-hairpin the only energetically favored structure to fold. The unfolded state of this peptide is populated with conformations with non-native intrapeptide interactions. This peptide goes through fully hydrated conformations to eliminate non-native interactions before folding into a beta-hairpin. The folding of a beta-hairpin starts with side-chain interactions, which bring two strands together to form interstrand hydrogen bonds. The unfolding of the beta-hairpin is not simply the reverse of the folding process. Comparing unfolding simulations using MD and SGMD methods demonstrate that SGMD simulations can qualitatively reproduce the kinetics of the peptide system.

Amino Acid Sequence↗
PubMed1998

Barstar has a highly dynamic hydrophobic core: evidence from molecular dynamics simulations and nuclear magnetic resonance relaxation data.

The dynamic behavior of the ribonuclease inhibitor barstar has been investigated by molecular dynamics (MD) simulations in explicit water. Two 2.5 ns MD simulations were performed, and an ensemble of 25 000 structures was generated. This ensemble reproduces the solution structures and is consistent with the experimental structural restraints from NMR spectroscopy. Reorientation of the backbone NH bond vectors and side chain methyl groups was monitored by calculation of autocorrelation functions and the generalized S2 order parameters. Order parameters derived for motion in the approximately 100 ps time scale were compared with those obtained from NMR relaxation measurements. Consistent with experiment, the backbone NH bond vectors were relatively rigid. In contrast, the side chain methyl groups exhibited a wide dynamic range, from restricted motion comparable to that of the backbone to rapid unrestricted motion. The order parameters for the methyl groups correlate well with their spatial separation from the backbone and are residue-type dependent. Smaller S2axis values were observed for leucine methyl groups, in part due to side chain hopping between two predominant rotamers (g+t and tg-). Motions such as the flipping of aromatic rings and the hopping of leucine side chains were prevalent within the hydrophobic core, suggesting that the core is fluid-like with low energy barriers between native conformational substates. Thus, our studies suggest that the entropy of the native state can be significant and should not be discounted in thermodynamic considerations of protein folding. On the basis of our results, the side chain motion represents the primary source of the residual entropy of the native state and entropic considerations based solely on backbone dynamics would be incomplete.

Bacillus↗
PubMed1997

Alamethicin channels - modelling via restrained molecular dynamics simulations.

Alamethicin channels have been modelled as approximately parallel bundles of transbilayer helices containing between N = 4 and 8 helices per bundle. Initial models were generated by in vacuo restrained molecular dynamics (MD) simulations, and were refined by 60 ps MD simulations with water molecules present within and at the mouths of the central pore. The helix bundles were stabilized by networks of H-bonds between intra-pore water molecules and Gln-7 side-chains. Channel conductances were predicted on the basis of pore radius profiles, and suggested that the N = 4 bundle formed an occluded pore, whereas pores with N > or = 5 helices per bundle were open. Continuum electrostatics calculations suggested that the N = 6 pore is cation-selective, whereas pores with N > or = 7 helices per bundle were predicted to be somewhat less ion-selective.

Alamethicin↗
PubMed2006

Molecular dynamics simulation of a pressure-driven liquid transport process in a cylindrical nanopore using two self-adjusting plates.

Fluid transport through a nanopore in a membrane was investigated by using a novel molecular dynamics approach proposed in this study. The advantages of this method, relative to dual-control-volume grand-canonical molecular dynamics method, are that it eliminates disruptions to the system dynamics that are normally created by inserting or deleting particles from control volumes, and that it functions well for dense systems due to the number of particles being fixed in the system. Using the proposed method, we examined liquid argon transport through a nanopore by performing nonequilibrium molecular dynamics (NEMD) simulations under different back pressures. Validation of the code was performed by comparing simulation results to published experimental data obtained under equilibrium conditions. NEMD results show that constant pressure difference across the membrane was readily achieved.

Computer Simulation↗
PubMed2005

MM/PBSA analysis of molecular dynamics simulations of bovine beta-lactoglobulin: free energy gradients in conformational transitions?

The pH-driven opening and closure of beta-lactoglobulin EF loop, acting as a lid and closing the internal cavity of the protein, has been studied by molecular dynamics (MD) simulations and free energy calculations based on molecular mechanics/Poisson-Boltzmann (PB) solvent-accessible surface area (MM/PBSA) methodology. The forms above and below the transition pH differ presumably only in the protonation state of residue Glu89. MM/PBSA calculations are able to reproduce qualitatively the thermodynamics of the transition. The analysis of MD simulations using a combination of MM/PBSA methodology and the colony energy approach is able to highlight the driving forces implied in the transition. The analysis suggests that global rearrangements take place before the equilibrium local conformation is reached. This conclusion may bear general relevance to conformational transitions in all lipocalins and proteins in general.

Animals↗
PubMed2001

Molecular dynamics simulations of the insertion of two ideally amphipathic lytic peptides LK(15) and LK(9) in a 1,2-dimyristoylphosphatidylcholine monolayer.

We present here the results of 1-ns molecular dynamics (MD) simulations of two ideally amphipathic lytic peptides, namely LK(15) and LK(9), in a 1,2-dimyristoylphosphatidylcholine monolayer with two different cross-sectional areas per lipid of 80 A(2) (loose film) and 63 A(2) (tight standard film). These peptides are lytic, ideally amphipathic with a minimalist composition L(i)K(j) and the following sequences: H(2)N-KLLKLLLKLLLKLLK-CO-Ph for LK(15) and H(2)N-KLKLKLKLK-CO-Ph for LK(9). From experimental data, LK(15) exhibits an alpha-helical secondary structure, whereas LK(9) was found to form antiparallel beta-sheets at the interface of a DMPC monolayer. Whatever the specific lipid surface is, the two peptides exhibit very different behavior: the alpha-helix inserts deeply into the monolayer whereas the beta-sheeted peptide stays at the surface within the upper polar part of the monolayer. In all cases, a loose monolayer (80 A(2)) results in noticeable artifacts whereas a monolayer with standard specific surface leads to very reliable behavior well in accordance with experimental data. Despite their different insertion depth, the two peptides exhibit identical lytic efficiency. This is very likely a direct consequence of the very strong Van der Waals interactions between the fatty alkyl chains of the lipids and the highly lipophilic lower part of the peptide, resulting in an identical thinning of the two monolayers.

Amino Acid Sequence↗
PubMed2002

Molecular dynamics simulations of protein folding from the transition state.

Putative transition-state ensemble (TSE) conformations of src SH3 were identified by monitoring the deviation from the experimental phi values along molecular dynamics (MD) simulations of unfolding. Sixty MD trajectories (for a total of about 7 micros) were then started from the putative TSE. About one-half of the 60 runs reached the folded state while unfolding was observed in the remaining half of the runs. This result validates phi-value analysis as an approach to obtain structural information on the transition state. It also demonstrates that an atomic resolution description of the TSE can be extracted from MD simulations. All conformations in the TSE have the central three-stranded beta-sheet formed in agreement with experimental data. An elongation of strand beta 2 as well as non-native side-chain interactions between the diverging turn and the distal hairpin are observed. The simulation results indicate that the tight packing of the side chains between the diverging turn and the distal hairpin is a necessary condition for rapid folding. Contacts between residues in the most structured element of the TSE, the central beta-sheet, are kinetically more important than those between the N- and C-terminal strands.

Computer Simulation↗
PubMed2004

Molecular dynamics simulations of the 136 unique tetranucleotide sequences of DNA oligonucleotides. I. Research design and results on d(CpG) steps.

We describe herein a computationally intensive project aimed at carrying out molecular dynamics (MD) simulations including water and counterions on B-DNA oligomers containing all 136 unique tetranucleotide base sequences. This initiative was undertaken by an international collaborative effort involving nine research groups, the "Ascona B-DNA Consortium" (ABC). Calculations were carried out on the 136 cases imbedded in 39 DNA oligomers with repeating tetranucleotide sequences, capped on both ends by GC pairs and each having a total length of 15 nucleotide pairs. All MD simulations were carried out using a well-defined protocol, the AMBER suite of programs, and the parm94 force field. Phase I of the ABC project involves a total of approximately 0.6 mus of simulation for systems containing approximately 24,000 atoms. The resulting trajectories involve 600,000 coordinate sets and represent approximately 400 gigabytes of data. In this article, the research design, details of the simulation protocol, informatics issues, and the organization of the results into a web-accessible database are described. Preliminary results from 15-ns MD trajectories are presented for the d(CpG) step in its 10 unique sequence contexts, and issues of stability and convergence, the extent of quasiergodic problems, and the possibility of long-lived conformational substates are discussed.

Base Sequence↗
PubMed2006

Coarse-grained molecular dynamics simulations of a rotating bacterial flagellum.

Many types of bacteria propel themselves using elongated structures known as flagella. The bacterial flagellar filament is a relatively simple and well-studied macromolecular assembly, which assumes different helical shapes when rotated in different directions. This polymorphism enables a bacterium to switch between running and tumbling modes; however, the mechanism governing the filament polymorphism is not completely understood. Here we report a study of the bacterial flagellar filament using numerical simulations that employ a novel coarse-grained molecular dynamics method. The simulations reveal the dynamics of a half-micrometer-long flagellum segment on a timescale of tens of microseconds. Depending on the rotation direction, specific modes of filament coiling and arrangement of monomers are observed, in qualitative agreement with experimental observations of flagellar polymorphism. We find that solvent-protein interactions are likely to contribute to the polymorphic helical shapes of the filament.

Bacteria↗
PubMed2001

Extending the capabilities of targeted molecular dynamics: simulation of a large conformational transition in plasminogen activator inhibitor 1.

Plasminogen activator inhibitor type 1 (PAI-1) is an inhibitor of plasminogen activators such as tissue-type plasminogen activator or urokinase-type plasminogen activator. For this molecule, different conformations are known. The inhibiting form that interacts with the proteinases is called the active form. The noninhibitory, noncleavable form is called the latent form. X-ray and modeling studies have revealed a large change in position of the reactive center loop (RCL), responsible for the interaction with the proteinases, that is inserted into a beta-sheet (s4A) in the latent form. The mechanism underlying this spontaneous conformational change (half-life = 2 h at 37 degrees C) is not known in detail. This investigation attempts to predict a transition path from the active to the latent structure at the atomic level, by using simulation techniques. Together with targeted molecular dynamics (TMD), a plausible assumption on a rigid body movement of the RCL was applied to define an initial guess for an intermediate. Different pathways were simulated, from the active to the intermediate, from the intermediate to the latent structure and vice versa under different conditions. Equilibrium simulations at different steps of the path also were performed. The results show that a continuous pathway from the active to the latent structure can be modeled. This study also shows that this approach may be applied in general to model large conformational changes in any kind of protein for which the initial and final three-dimensional structure is known.

Computer Simulation↗