The contribution of electrostatic interactions to the collapse of oligoglycine in water.

Protein solubility and conformational stability are a result of a balance of interactions both within a protein and between protein and solvent. The electrostatic solvation free energy of oligoglycines, models for the peptide backbone, becomes more favorable with an increasing length, yet longer peptides collapse due to the formation of favorable intrapeptide interactions between CO dipoles, in some cases without hydrogen bonds. The strongly repulsive solvent cavity formation is balanced by van der Waals attractions and electrostatic contributions. In order to investigate the competition between solvent exclusion and charge interactions we simulate the collapse of a long oligoglycine comprised of 15 residues while scaling the charges on the peptide from zero to fully charged. We examine the effect this has on the conformational properties of the peptide. We also describe the approximate thermodynamic changes that occur during the scaling both in terms of intrapeptide potentials and peptide-water potentials, and estimate the electrostatic solvation free energy of the system.

Protein hydration density: theory, simulations and crystallography.

Models of protein hydration are becoming increasingly more accurate in comparison with experimental data. The recent success of these models implies that the major features of the solvation layers are dominated by local correlations and that such correlations are universal. The excellent agreement between theoretical and experimental solvent electron density radial distributions marks a significant success in our ability to accurately model macromolecular hydration.

Characterizing global substates of myoglobin.

BACKGROUND: The massive amount of information generated from current molecular dynamics simulations makes the data difficult to analyze efficiently. Principal component analysis has been used for almost a century to detect and characterize data relationships and to reduce the dimensionality for problems in many fields. Here, we present an adaptation of principal component analysis using a partial singular value decomposition (SVD) for investigating both the localized and global motions of macromolecules. RESULTS: Configuration space projections from the SVD analysis of a variety of myoglobin simulations are used to characterize the dynamics of the protein. This technique reveals new dynamical motifs, which quantify proposed hierarchical structures of conformational substates for proteins and provide a means by which configuration space sampling efficiency may be probed. The SVD clearly shows that solvent effects facilitate transitions between global conformational substates for myoglobin molecular dynamics simulations. Lyapunov exponents calculated from the configuration space divergence of 15 trajectories agree with previous predictions for the chaotic behavior of complex protein systems. CONCLUSIONS: Configuration space projections provide invaluable information about protein motions that would be extremely difficult to obtain otherwise. While the configuration space for myoglobin is quite large, it does have structure. Our analysis of this structure shows that the protein hops between a number of distinct global conformational states, much like the local behavior observed for an individual residue.

Stabilities of double- and triple-strand helical nucleic acids.

In this selected literature survey, we have seen that the stabilities of duplexes and triplexes are governed by the vertical base stacking, the horizontal specific base-paired H-bonding and the environmental parameters. The entropic contribution in the solvation/desolvation process is important in driving the aggregation of NA strands and duplex formation, but base stacking and specific H-bonding maintain the helical order. Triplex formation shares most of the physical environmental prerequisites with those of duplex NAs. However, some additional environmental conditions are often needed. Only in low pH solution is the polycytidylic strand protonated and, thus, it is possible for the strand to bind to a G.C duplex sequence to give the C+(G.C) triplex. High ionic strength is often necessary for the screening of inter-phosphate repulsion due to the high linear charge density in triplexes. The presence of specific counterions is important for complexation. In the absence of negative supercoiling, existence of an intramolecular triplex is rare except under very acidic conditions for the formation of C+(G.C)-type intramolecular triplex. As expected, the stabilities of both inter- and intramolecular triplexes increase with sequence length. The thermodynamic principles of helix-coil transition of oligo-duplex may be described by the van't Hoff relationship, which assumes a two-state cooperative melting profile. Thus, the enthalpy, entropy and free energy of transition can be evaluated from the experimental melting curves (e.g. OD, DSC). For polynucleotides, because of the non-two-state nature of transition, the simple van't Hoff relationship is no longer valid, and direct calorimetry is needed to obtain reliable thermodynamic parameters. The pH and salt concentration dependence of duplex stability can be formulated and derived from a van't Hoff equation. Base-stacking patterns are simple in duplexes but not so in triplexes due to the diversity in triplet schemes. The sequence dependence of base stacking for duplexes has been characterized and employed to predict the stability of an arbitrary sequence. In conclusion, the stability of duplex is relatively well-characterized by thermodynamic data in terms of both base stacking and specific H-bonding. Thermodynamic studies of triplexes have been far fewer in number. Oligonucleotides have found application in the detection and localization of a mRNA or its gene, the detection of bacterial or viral sequences, and the inhibition of the translation of mRNA and the transcription and replication of DNA (Englisch and Gauss, 1991). In a different approach, oligonucleotides have been targeted directly to a DNA duplex motif of a gene in order to inhibit the expression at the beginning of the transcriptional process.(ABSTRACT TRUNCATED AT 400 WORDS)

Modeling high-resolution hydration patterns in correlation with DNA sequence and conformation.

Hydration around the DNA fragment d(C5T5).(A5G5) is presented from two molecular dynamics simulations of 10 and 12 ns total simulation time. The DNA has been simulated as a flexible molecule with both the CHARMM and AMBER force fields in explicit solvent including counterions and 0.8 M additional NaCl salt. From the previous analysis of the DNA structure B-DNA conformations were found with the AMBER force-field and A-DNA conformations with CHARMM parameters. High-resolution hydration patterns are compared between the two conformations and between C.G and T.A base-pairs from the homopolymeric parts of the simulated sequence. Crystallographic results from a statistical analysis of hydration sites around DNA crystal structures compare very well with the simulation results. Differences between the crystal sites and our data are explained by variations in conformation, sequence, and limitations in the resolution of water sites by crystal diffraction. Hydration layers are defined from radial distribution functions and compared with experimental results. Excellent agreement is found when the measured experimental quantities are compared with the equivalent distribution of water molecules in the first hydration shell. The number of water molecules bound to DNA was found smaller around T.A base-pairs and around A-DNA as compared to B-DNA. This is partially offset by a larger number of water molecules in hydrophobic contact with DNA around T.A base-pairs and around A-DNA. The numbers of water molecules in minor and major grooves have been correlated with helical roll, twist, and inclination angles. The data more fully explain the observed B-->A transition at low humidity.

Structure and dynamics of the water around myoglobin.

The interplay between simulations at various levels of hydration and experimental observables has led to a picture of the role of solvent in thermodynamics and dynamics of protein systems. One of the most studied protein-solvent systems is myoglobin, which serves as a paradigm for the development of structure-function relationships in many biophysical studies. We review here some aspects of the solvation of myoglobin and the resulting implications. In particular, recent theoretical and simulation studies unify much of the diverse set of experimental results on water near proteins.

Selective elimination of interactions: a method for assessing thermodynamic contributions to ligand binding with application to rhinovirus antivirals.

A new method for evaluating the free energy of various physical interactions, such as hydrogen-bond, electrostatic, or van der Waals interactions, is presented. Rather than destroying or creating whole groups, selective (pairwise) interactions are eliminated from the total potential energy and the energy difference with the fully interacting system is evaluated. The exponential ensemble average of such an energy difference is then directly related to the corresponding free energy difference. This procedure is then applied to a rather large protein-ligand system involving the coat proteins of a human rhinovirus and an antiviral ligand. The results seem to indicate that a particular bent hydrogen bond between the ligand and protein system may not be favorable for binding. The method presented gives an estimate of the hydrogen bond free energy contribution with an available trajectory that was previously computed without the expenditure of sizeable computational resources such as recomputing a trajectory. This procedure is effective and efficient for computing the free energy for a given type of physical interaction. It can be used for calculating the binding energy differences for various interactions which can be used to guide the search for isosoluble synthetic targets.

On the mechanism of HRV-14 antiviral compounds: "slow growth" as a conformational search procedure.

We report a novel conformational search procedure that is used to investigate the binding mechanism of a member of the WIN class of antiviral compounds. A simple hypothesis of important residues in the binding site based on differences in drug-free and drug-bound X-ray structures along with more elaborate models, ultimately including the entire virus, is considered. Our search method is a variant of slow-growth molecular dynamics used in free energy simulations and gives rise to local motion in the protein backbone of up to 3 A. This technique involves the scaling of drug-protein interaction energies over time periods of 10-100 ps and gives rise to local motion in the protein backbone. In addition, we have used high-temperature dynamics with periodic quenching to generate low-energy conformations with backbone displacements in the crystallographic binding region of up to 7 A from the native structure. Mechanism of binding, hydrogen-bond stabilization of active-site conformations, concerted drug-protein motions, and the mode of virion stabilization are addressed in relation to our ligand induced and high-temperature conformational search procedures. A loop-cap like mechanism is consistent with the results of our study. A large movement of the "active-site" residues is shown to be theoretically possible and provides a greater access for entry of the drug into its binding pocket than seen in the available crystal structures.

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.

Integral equation approaches to structure and thermodynamics of aqueous salt solutions.

Results for free energy, entropy, enthalpy and internal energy of solvation for monovalent ions in water have been studied by comparing DRISM theory results to those of RISM and ARISM theories. The greatly improved dielectric behavior in the DRISM case enabled the examination of realistically modeled salts at finite concentrations. The link between solvent structure and the entropy of solvent co-spheres was examined. Finally comparison with the Born free energy equation shows its virtues and flaws due to ignoring cavity formation and asymmetric solvation terms which together always contribute significantly to the free energy of hydration of ions.

Comparison of the potentials of mean force for alanine tetrapeptide between integral equation theory and simulation.

The dielectrically consistent reference interaction site model (DRISM) integral equation theory is applied to determine the potential of mean force (PMF) for an alanine tetramer. A stochastic dynamics simulation of the alanine tetramer using this PMF is then compared with an explicit water molecular dynamics simulation. In addition, comparison is also done with simulations using other solvent models like the extended reference interaction site model (XRISM) theory, constant dielectric and linear distance-dependent dielectric models. The results show that the DRISM method offers a fairly accurate and computationally inexpensive alternative to explicit water simulations for studies on small peptides.

Systematic investigation of theories of transport in the Lennard-Jones fluid.

Three kinetic theories of transport are investigated for the single-species Lennard-Jones model fluid. Transport coefficients, including diffusion, shear, and bulk viscosity, are calculated from these theories for the Lennard-Jones fluid across the fluid regions of the phase diagram. The results are systematically compared against simulation. It is found that for each transport property considered, there is at least one theoretical result based on approximations that have been systematically derived from a first-principles starting point that is quantitatively useful over a wide range of densities and temperatures. To the authors' knowledge, this article constitutes the first such compendium of results for the Lennard-Jones model fluid that has been assembled.

Fast multipole methods for particle dynamics.

The growth of simulations of particle systems has been aided by advances in computer speed and algorithms. The adoption of O(N) algorithms to solve N-body simulation problems has been less rapid due to the fact that such scaling was only competitive for relatively large N. Our work seeks to find algorithmic modifications and practical implementations for intermediate values of N in typical use for molecular simulations. This article reviews fast multipole techniques for calculation of electrostatic interactions in molecular systems. The basic mathematics behind fast summations applied to long ranged forces is presented along with advanced techniques for accelerating the solution, including our most recent developments. The computational efficiency of the new methods facilitates both simulations of large systems as well as longer and therefore more realistic simulations of smaller systems.

Simple bond length dependence: a correspondence between reactive fluid theories.

Two elementary models of reactive fluids are examined, the first being a standard construction assuming molecular dissociation at infinite separation; the second is an open mixture of nondissociative molecules and free atoms in which the densities of free atoms and molecules are coupled. An approximation to the density of molecules, to low order in site density, is derived in terms of the classical associating fluid theory variously described by Wertheim [J. Chem. Phys. 87, 7323 (1987)] and Stell [Physica A 231, 1 (1996)]. The results are derived for a fluid of dimerizing hard spheres, and predict dependence of the molecular density on the total site density, the hard sphere diameter, and the bond length of the dimer. The results for the two reactive models are shown to be qualitatively similar, and lead to equivalent predictions of the molecular density for the infinitely short and infinitely long bond lengths.

The theoretical basis of universal identification systems for bacteria and viruses.

It is shown that the presence/absence pattern of 1000 random oligomers of length 12-13 in a bacterial genome is sufficiently characteristic to readily and unambiguously distinguish any known bacterial genome from any other. Even genomes of extremely closely-related organisms, such as strains of the same species, can be thus distinguished. One evident way to implement this approach in a practical assay is with hybridization arrays. It is envisioned that a single universal array can be readily designed that would allow identification of any bacterium that appears in a database of known patterns. We performed in silico experiments to test this idea. Calculations utilizing 105 publicly-available completely-sequenced microbial genomes allowed us to determine appropriate values of the test oligonucleotide length, n, and the number of probe sequences. Randomly chosen n-mers with a constant G + C content were used to form an in silico array and verify (a) how many n-mers from each genome would hybridize on this chip, and (b) how different the fingerprints of different genomes would be. With the appropriate choice of random oligomer length, the same approach can also be used to identify viral or eukaryotic genomes.

A connected-cluster of hydration around myoglobin: correlation between molecular dynamics simulations and experiment.

An analysis of a molecular dynamics simulation of metmyoglobin in an explicit solvent environment of 3,128 water molecules has been performed. Both statics and dynamics of the protein-solvent interface are addressed in a comparison with experiment. Three-dimensional density distributions, temperature factors, and occupancy weights are computed for the solvent by using the trajectory coordinates. Analysis of the hydration leads to the localization of more than 500 hydration sites distributed into multiple layers of solvation located between 2.6 and 6.8 A from the atomic protein surface. After locating the local solvent density maxima or hydration sites we conclude that water molecules of hydration positions and hydration sites are distinct concepts. Both global and detailed properties of the hydration cluster around myoglobin are compared with recent neutron and X-ray data on myoglobin. Questions arising from differences between X-ray and neutron data concerning the locations of the protein-bound water are investigated. Analysis of water site differences found from X-ray and neutron experiments compared with our simulation shows that the simulation gives a way to unify the hydration picture given by the two experiments.

Distribution function implied dynamics versus residence times and correlations: solvation shells of myoglobin.

The dynamics of water at the protein-solvent interface is investigated through the analysis of a molecular dynamics simulation of metmyoglobin in explicit aqueous environment. Distribution implied dynamics, harmonic and quasi-harmonic, are compared with the simulated macroscopic dynamics. The distinction between distinguishable solvent molecules and hydration sites developed in the previous paper is used. The simulated hydration region within 7 A from the protein surface is analyzed using a set of 551 hydration sites characterized by occupancy weights and temperature B-factors determined from the simulation trajectory. The precision of the isotropic harmonic and anisotropic harmonic models for the description of proximal solvent fluctuations is examined. Residence times and dipole reorientation times of water around the protein surface are compared with NMR and ESR results. A correlation between diffraction experiment quantities such as the occupancy weights and temperature factors and the residence and correlation times resulting from magnetic resonance experiments is found via comparison with simulation.

Sodium and chlorine ions as part of the DNA solvation shell.

The distribution of sodium and chlorine ions around DNA is presented from two molecular dynamics simulations of the DNA fragment d(C(5)T(5)). (A(5)G(5)) in explicit solvent with 0.8 M additional NaCl salt. One simulation was carried out for 10 ns with the CHARMM force field that keeps the DNA structure close to A-DNA, the other for 12 ns with the AMBER force field that preferentially stabilizes B-DNA conformations (, Biophys. J. 75:134-149). From radial distributions of sodium and chlorine ions a primary ion shell is defined. The ion counts and residence times of ions within this shell are compared between conformations and with experiment. Ordered sodium ion sites were found in minor and major grooves around both A and B-DNA conformations. Changes in the surrounding hydration structure are analyzed and implications for the stabilization of A-DNA and B-DNA conformations are discussed.