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PubMed2004

High-order averaging schemes with error bounds for thermodynamical properties calculations by molecular dynamics simulations.

We introduce high-order formulas for the computation of statistical averages based on the long-time simulation of molecular dynamics trajectories. In some cases, this allows us to significantly improve the convergence rate of time averages toward ensemble averages. We provide some numerical examples that show the efficiency of our scheme. When trajectories are approximated using symplectic integration schemes (such as velocity Verlet), we give some error bounds that allow one to fix the parameters of the computation in order to reach a given desired accuracy in the most efficient manner.

Journal Article↗
PubMed2004

CHARMM fluctuating charge force field for proteins: II protein/solvent properties from molecular dynamics simulations using a nonadditive electrostatic model.

A fluctuating charge (FQ) force field is applied to molecular dynamics simulations for six small proteins in explicit polarizable solvent represented by the TIP4P-FQ potential. The proteins include 1FSV, 1ENH, 1PGB, 1VII, 1H8K, and 1CRN, representing both helical and beta-sheet secondary structural elements. Constant pressure and temperature (NPT) molecular dynamics simulations are performed on time scales of several nanoseconds, the longest simulations yet reported using explicitly polarizable all-atom empirical potentials (for both solvent and protein) in the condensed phase. In terms of structure, the FQ force field allows deviations from native structure up to 2.5 A (with a range of 1.0 to 2.5 A). This is commensurate to the performance of the CHARMM22 nonpolarizable model and other currently existing polarizable models. Importantly, secondary structural elements maintain native structure in general to within 1 A (both helix and beta-strands), again in good agreement with the nonpolarizable case. In qualitative agreement with QM/MM ab initio dynamics on crambin (Liu et al. Proteins 2001, 44, 484), there is a sequence dependence of average condensed phase atomic charge for all proteins, a dependence one would anticipate considering the differing chemical environments around individual atoms; this is a subtle quantum mechanical feature captured in the FQ model but absent in current state-of-the-art nonpolarizable models. Furthermore, there is a mutual polarization of solvent and protein in the condensed phase. Solvent dipole moment distributions within the first and second solvation shells around the protein display a shift towards higher dipole moments (increases on the order of 0.2-0.3 Debye) relative to the bulk; protein polarization is manifested via the enhanced condensed phase charges of typical polar atoms such as backbone carbonyl oxygens, amide nitrogens, and amide hydrogens. Finally, to enlarge the sample set of proteins, gas-phase minimizations and 1 ps constant temperature simulations are performed on various-sized proteins to compare to earlier work by Kaminsky et al. (J Comp Chem 2002, 23, 1515). The present work establishes the feasibility of applying a fully polarizable force field for protein simulations and demonstrates the approach employed in extending the CHARMM force field to include these effects.

Computational Biology↗
PubMed2006

Molecular-dynamics simulations with explicit hydrodynamics II: on the collision of polymers with molecular obstacles.

We present a study of the dynamics of single polymers colliding with molecular obstacles using Molecular-dynamics simulations. In concert with these simulations we present a generalized polymer-obstacle collision model which is applicable to a number of collision scenarios. The work focusses on three specific problems: i) a polymer driven by an external force colliding with a fixed microscopic post; ii) a polymer driven by a (plug-like) fluid flow colliding with a fixed microscopic post; and iii) a polymer driven by an external force colliding with a free polymer. In all three cases, we present a study of the length-dependent dynamics of the polymers involved. The simulation results are compared with calculations based on our generalized collision model. The generalized model yields analytical results in the first two instances (cases i) and ii)), while in the polymer-polymer collision example (case iii)) we obtain a series solution for the system dynamics. For the case of a polymer-polymer collision we find that a distinct V-shaped state exists as seen in experimental systems, though normally associated with collisions with multiple polymers. We suggest that this V-shaped state occurs due to an effective hydrodynamic counter flow generated by a net translational motion of the two-chain system.

Adsorption↗
PubMed2001

Molecular dynamics simulations of human rhinovirus and an antiviral compound.

The human rhinovirus 14 (HRV14) protomer, with or without the antiviral compound WIN 52084s, was simulated using molecular dynamics and rotational symmetry boundary conditions to model the effect of the entire icosahedral capsid. The protein asymmetrical unit, comprising four capsid proteins (VP1, VP2, VP3, and VP4) and two calcium ions, was solvated both on the exterior and the interior to fill the inside of the capsid. The stability of the simulations of this large system (~800 residues and 6,650 water molecules) is comparable to more conventional globular protein simulations. The influence of the antiviral compound on compressibility and positional fluctuations is reported. The compressibility, estimated from the density fluctuations in the region of the binding pocket, was found to be greater with WIN 52084s bound than without the drug, substantiating previous computations on reduced viral systems. An increase in compressibility correlates with an entropically more favorable system. In contrast to the increase in density fluctuations and compressibility, the positional fluctuations decreased dramatically for the external loops of VP1 and the N-terminus of VP3 when WIN 52084s is bound. Most of these VP1 and VP3 loops are found near the fivefold axis, a region whose mobility was not considered in reduced systems, but can be observed with this simulation of the full viral protomer. Altered loop flexibility is consistent with changes in proteolytic sensitivity observed experimentally. Moreover, decreased flexibility in these intraprotomeric loops is noteworthy since the externalization of VP4, part of VP1, and RNA during the uncoating process is thought to involve areas near the fivefold axis. Both the decrease in positional fluctuations at the fivefold axis and the increase in compressibility near the WIN pocket are discussed in relationship to the antiviral activity of stabilizing the virus against uncoating.

Antiviral Agents↗
PubMed2003

Mechanical unfolding of a titin Ig domain: structure of transition state revealed by combining atomic force microscopy, protein engineering and molecular dynamics simulations.

Titin I27 shows a high resistance to unfolding when subject to external force. To investigate the molecular basis of this mechanical stability, protein engineering Phi-value analysis has been combined with atomic force microscopy to investigate the structure of the barrier to forced unfolding. The results indicate that the transition state for forced unfolding is significantly structured, since highly destabilising mutations in the core do not affect the force required to unfold the protein. As has been shown before, mechanical strength lies in the region of the A' and G-strands but, contrary to previous suggestions, the results indicate clearly that side-chain interactions play a significant role in maintaining mechanical stability. Since Phi-values calculated from molecular dynamics simulations are the same as those determined experimentally, we can, with confidence, use the molecular dynamics simulations to analyse the structure of the transition state in detail, and are able to show loss of interactions between the A' and G-strands with associated A-B and E-F loops in the transition state. The key event is not a simple case of loss of hydrogen bonding interactions between the A' and G-strands alone. Comparison with Phi-values from traditional folding studies shows differences between the force and "no-force" transition states but, nevertheless, the region important for kinetic stability is the same in both cases. This explains the correspondence between hierarchy of kinetic stability (measured in stopped-flow denaturant studies) and mechanical strength in these titin domains.

Computer Simulation↗
PubMed1999

Restraint-driven formation of alpha-helical coiled coils in molecular dynamics simulations.

The alpha-helical coiled coil motif is among the first characterized and widely found architecture of protein structures. We report here a fast and reliable approach of simulated annealing molecular dynamics (SA/MD) for predicting the three-dimensional structures of various alpha-helical coiled coils of heptad repeat. One key element of our simulation involves a geometric restraint requiring residues occupying the first and fourth positions of the heptad to orient to the angle of their respective statistical average derived from a survey of coiled-coil structures deposited in the Protein Data Bank. Another is the incorporation of subunit rotation and inversion operations for generating symmetrized protein assemblies during the dynamics simulations. The procedure is fully automated and can be applied to different oligomerization states of identical subunits, as well as both parallel and antiparallel arrangements. Despite simplicity, the formation of five coiled-coil prototype systems driven by the restraint-based SA/MD approach shows that the level of prediction accuracy achieved previously by more elaborate procedures can be retained. The present work thus provides validation of a simulation approach that can be employed to utilize a wide variety of knowledge-based geometric restraints for structural prediction of symmetrical or pseudo-symmetrical protein systems.

Amino Acid Sequence↗
PubMed1992

Molecular dynamics simulation of bovine prothrombin fragment 1 in the presence of calcium ions.

Early solvation-induced structural reorganization of calcium prothrombin fragment 1 is simulated with molecular dynamics. Initial coordinates are those of the 2.2-A resolution crystal structure [Soriano-Garcia, M., Padmanabhan, K., de Vos, A. M., & Tulinsky, A. (1992) Biochemistry 31, 2554-2556]. The molecular dynamics code AMBER, appropriately modified to include long-range (less than or equal to 22.0 A) ionic forces, was employed. The solution structure appears to equilibrate within 100 ps. Although minor changes are seen in various structural domains, the early solution structure basically maintains an intricate network of nine gamma-carboxyglutamic acid (Gla) residues encapsulating seven calcium ions. However, the Gla domain moves with respect to the kringle domain. This motion is mainly due to the movement of Ser34-Leu35 that appears to be a flexible hinge between the domains. The N-terminus of Ala 1 is in a tightly bound complex with three Gla residues that remains stable in the solution structure when the long-range electrostatic cutoff is employed and the near planar alignment of the seven calcium ions is only slightly distorted. The simulation structure is discussed in terms of experiments that studied calcium ion-induced quenching of the intrinsic fluorescence, protection of the N-terminal amino group from acetylation by calcium ions, chemical modification of the N-terminus to a trinitrophenyl derivative, and the possibility of a calcium-binding site(s) in the kringle domain.

Amino Acid Sequence↗
PubMed1991

Molecular dynamics simulations of the cytochrome c3-rubredoxin complex from Desulfovibrio vulgaris.

Molecular dynamics simulations have been carried out on the complex formed between the tetraheme cytochrome c3 and the iron protein rubredoxin from the sulfate-reducing bacterium Desulfovibrio vulgaris. These simulations were performed both with explicit solvent water molecules included, and without solvent molecules using a distance-dependent dielectric constant to approximate the screening effects of solvent. The results of both simulations are strikingly different, indicating that the representation of environmental effects is important in such simulations. For example, a striking adaptation of the two proteins seen in the nonsolvated simulation is not seen when explicit solvent water is included; in fact, the complex appears to become weaker in the solvated simulation. Nonetheless, the iron-iron distance decreases more significantly in the solvated simulation than in the nonsolvated simulation. It was found that in both cases molecular dynamics optimized the structures further than energy minimization alone.

Computer Simulation↗
PubMed1994

Molecular dynamics simulations suggest that the Eco RI kink is an example of molecular strain.

The energy surface in the vicinity of the "Eco RI kink" was investigated by conducting both in vacuo molecular dynamics simulations as well as a simulation with explicit solvent. The in vacuo simulations used the "all atom" AMBER 3.0 force field with a distant dependent dielectric function and "hydrated" counter ions while the simulation with explicit solvent used the AMBER 4.0 force field, fully charged phosphates and counter ions and a dielectric constant of 1.0. The thrust of the simulations was to discriminate between two models of the energy surface of the deformed DNA as found in the recognition complex with Eco RI endonuclease. In the intrinsic model, the kinked DNA is a local minimum of the energy surface intrinsic to the DNA itself while in the strained model there is no significant energy barrier separating kinked and regular B-DNA. The two models have significant implications for theories of indirect recognition of DNA based on sequence-dependent deformability. The simulations suggest that the Eco RI-kinked structure is an example of molecular strain because it is not near a minimum of any of the potential energy functions examined. The simulations leave the question of an energy barrier somewhat open and raise the possibility that the Eco RI kink is at (or near) a point of dynamic instability of the energy surface (either a true maximum or a saddle point).

Base Sequence↗
PubMed2006

Molecular dynamics simulations to aid the rational design of organic friction modifiers.

Molecular dynamics simulations were performed under conditions of constant volume and temperature and of constant pressure and temperature to elucidate the structure activity relationships of a series of non-ionic surfactant molecules derived from vegetable fat and employed as friction modifiers in commercial engine oils. The simulations show the extent to which intermolecular hydrogen bonding is important in determining the stability of the monolayer formed by the surfactant molecules and show that mono-alkanoyl glyceride molecules are able to pack more efficiently, forming significantly more intermolecular hydrogen bonds and occupying approximately half the volume needed by di-alkanoyl glyceride molecules. Density profiles are presented which show significant mixing of the hydrophobic tail groups and a non-polar solvent. The distribution of torsion angles in the tail groups shows that the conformation is consistent with a liquid at finite temperature rather than a crystal structure. The measured friction coefficients of equimolar solutions of the glycerides show that the efficacy as friction modifiers varies in the order mono-, di- and the tri-oleyl glyceride, which is consistent with the efficacy of film formation predicted by the molecular dynamics calculations.

Computer Simulation↗
PubMed2000

Local-spin-density-approximation molecular-dynamics simulations of dense deuterium.

Local-spin-density-approximation molecular-dynamics simulations of deuterium in the dissociating regime are presented, with a particular emphasis on the molecular phase of two isochores corresponding for deuterium to V=6 cm(3)/mole, rho=0.670 g/cm(3) and V=4 cm(3)/mole, rho=1 g/cm(3). It is shown that the transition from the molecular regime, well described by the local-spin-density-approximation functional, to the dissociated regime where previous local-density-approximation results are recovered, comes with a negative curvature deltaP/deltaT<0 in the isochore. We show that this effect is not enough to explain the large compressibility measured in the laser experiments [L. B. DaSilva et al., Phys. Rev. Lett. 78, 483 (1997); G. W. Collins et al., Science 281, 1178 (1998); P. Celliers et al., Phys. Rev. Lett. 84, 5564 (2000)].

Journal Article↗
PubMed2006

Molecular dynamics simulation study of water adsorption on hydroxylated graphite surfaces.

In this paper, we present results from molecular dynamic simulations devoted to the characterization of the interaction between water molecules and hydroxylated graphite surfaces considered as models for surfaces of soot emitted by aircraft. The hydroxylated graphite surfaces are modeled by anchoring several OH groups on an infinite graphite plane. The molecular dynamics simulations are based on a classical potential issued from quantum chemical calculations. They are performed at three temperatures (100, 200, and 250 K) to provide a view of the structure and dynamics of water clusters on the model soot surface. These simulations show that the water-OH sites interaction is quite weak compared to the water-water interaction. This leads to the clustering of the water molecules above the surface, and the corresponding water aggregate can only be trapped by the OH sites when the temperature is sufficiently low, or when the density of OH sites is sufficiently high.

Journal Article↗
PubMed2005

Molecular dynamics simulation of amphiphilic dimers at a liquid-vapor interface.

Molecular dynamics simulations are utilized to simulate a model liquid-vapor-amphiphile system. Amphiphilic surfactant molecules are modeled as dimers composed of a hydrophilic head and a hydrophobic tail. Three dimer models with three different head sizes and two different head-to-tail size ratios are studied. The surfactant molecules distribute preferentially at the interfaces at low concentrations and form micelles in the bulk liquid phase as the concentration increases. We find that the surface tension decreases as molecular concentration increases, with a reduction in the rate of decrease after micellization occurs. The extent to which a surfactant can reduce the surface tension at a given concentration is found to depend on the head size. Furthermore, the head size and concentration dependence of the surfactant tilt-angle distribution is studied and compared to experimental data.

Journal Article↗
PubMed1994

Canonical analysis of correlated atomic motions in DNA from molecular dynamics simulation.

We report a method for analyzing atomic correlated motions in biopolymers from trajectories obtained by molecular dynamics simulation. A correlation coefficient based on the canonical analysis of data is defined which is independent on the relative orientation of atomic displacement. To illustrate the method we studied correlation between positional fluctuations of protons in the double-stranded self complementary oligonucleotide d(CTGAT-CAG), deduced from a 200 ps molecular dynamics simulation in the presence of explicit water molecules and counterions. It is found that on this time scale the motions of protons belonging to different residues are poorly coupled while the motion of a base proton is correlated to the motion of the sugar ring protons of the same nucleotide. Such a method may be generalized to study correlated motions of two distinct domains of a macro-molecule.

Computer Simulation↗
PubMed2000

Nonequilibrium molecular dynamics simulations of heat flow in one-dimensional lattices

We study the use of the Evans nonequilibrium molecular dynamics (NEMD) heat flow algorithm for the computation of the heat conductivity in one-dimensional lattices. For the well-known Fermi-Pasta-Ulam model, it is shown that when the heat field strength is greater than a certain critical value (which depends on the system size) solitons can be generated in molecular dynamics simulations starting from random initial conditions. Such solitons are stable and travel with supersonic speeds. For smaller heat fields, no solitons are generated in the molecular dynamics simulations; the heat conductivity obtained via the NEMD algorithm increases monotonically with the size of the system.

Journal Article↗
PubMed2005

Molecular dynamics simulations and free energy calculations of netropsin and distamycin binding to an AAAAA DNA binding site.

Molecular dynamics simulations have been performed on netropsin in two different charge states and on distamycin binding to the minor groove of the DNA duplex d(CGCGAAAAACGCG).d(CGCGTTTTTCGCG). The relative free energy of binding of the two non-covalently interacting ligands was calculated using the thermodynamic integration method and reflects the experimental result. From 2 ns simulations of the ligands free in solution and when bound to DNA, the mobility and the hydrogen-bonding patterns of the ligands were studied, as well as their hydration. It is shown that even though distamycin is less hydrated than netropsin, the loss of ligand-solvent interactions is very similar for both ligands. The relative mobilities of the ligands in their bound and free forms indicate a larger entropic penalty for distamycin when binding to the minor groove compared with netropsin, partially explaining the lower binding affinity of the distamycin molecule. The detailed structural and energetic insights obtained from the molecular dynamics simulations allow for a better understanding of the factors determining ligand-DNA binding.

Anti-Bacterial Agents↗
PubMed1996

Proton transport across transient single-file water pores in a lipid membrane studied by molecular dynamics simulations.

To test the hypothesis that water pores in a lipid membrane mediate the proton transport, molecular dynamic simulations of a phospholipid membrane, in which the formation of a water pore is induced, are reported. The probability density of such a pore in the membrane was obtained from the free energy of formation of the pore, which was computed from the average force needed to constrain the pore in the membrane. It was found that the free energy of a single file of water molecules spanning the bilayer is 108(+/-10) kJ/mol. From unconstrained molecular dynamic simulations it was further deduced that the nature of the pore is very transient, with a mean lifetime of a few picoseconds. The orientations of water molecules within the pore were also studied, and the spontaneous translocation of a turning defect was observed. The combined data allowed a permeability coefficient for proton permeation across the membrane to be computed, assuming that a suitable orientation of the water molecules in the pore allows protons to permeate the membrane relatively fast by means of a wirelike conductance mechanism. The computed value fits the experimental data only if it is assumed that the entry of the proton into the pore is not rate limiting.

Biological Transport↗