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PubMed2004

Synchronization of trajectories in canonical molecular-dynamics simulations: observation, explanation, and exploitation.

For two methods commonly used to achieve canonical-ensemble sampling in a molecular-dynamics simulation, the Langevin thermostat and the Andersen [H. C. Andersen, J. Chem. Phys. 72, 2384 (1980)] thermostat, we observe, as have others, synchronization of initially independent trajectories in the same potential basin when the same random number sequence is employed. For the first time, we derive the time dependence of this synchronization for a harmonic well and show that the rate of synchronization is proportional to the thermostat coupling strength at weak coupling and inversely proportional at strong coupling with a peak in between. Explanations for the synchronization and the coupling dependence are given for both thermostats. Observation of the effect for a realistic 97-atom system indicates that this phenomenon is quite general. We discuss some of the implications of this effect and propose that it can be exploited to develop new simulation techniques. We give three examples: efficient thermalization (a concept which was also noted by Fahy and Hamann [S. Fahy and D. R. Hamann, Phys. Rev. Lett. 69, 761 (1992)]), time-parallelization of a trajectory in an infrequent-event system, and detecting transitions in an infrequent-event system.

Algorithms↗
PubMed1997

Molecular dynamics simulations of the docking of substituted N5-deazapterins to dihydrofolate reductase.

Orientations of the deazapterin ring and the conformational preferences of groups appended to the deazapterin ring in a set of 8-substituted deazapterin cations docked into the dihydrofolate reductase (DHFR) binding site have been investigated using a methodology based on the simulated annealing technique within molecular dynamics (MD) simulations. Of five possible binding pockets for the 8-substituents, identified from a preliminary manual docking study, one has been definitively eliminated after an analysis of MD trajectories, while another remains uncertain. Using a new method based on standard thermodynamic cycles and a linear approximation of polar and non-polar free energy contributions from MD averages, binding affinities of the different ligands in each binding site have been correlated with experimental dissociation constants. The study has provided insights into structure-activity relationships for use in the design of modified inhibitors of DHFR.

Binding Sites↗
PubMed2007

Molecular dynamics simulation of the reaction of hydration of formaldehyde using a potential based on solute-solvent interaction energy components.

Molecular dynamics simulations of aqueous solutions at infinite dilution of the reaction of water with formaldehyde, H(2)O + H(2)CO --> H(2)C(OH)(2), were performed using Lennard-Jones 12-6-1 potentials to describe the solute-solvent interactions, and TIP3P to describe the water-water interactions. The Morokuma decomposition scheme of ab initio interaction energies at the SCF level and the dispersion component at MP2 level were used to reproduce the molecular parameters of the solute-water interaction potential. The results show that the functions that use the EX-PL-DIS-ES interaction model to describe the solvation of the reactant and product systems lead to good values of the reaction (DeltaG) and activation (DeltaG(#)) free energy as compared with those from using AMBER-derived parameters, and with the available theoretical and experimental data.

Journal Article↗
PubMed2003

Protein engineering to improve the thermostability of glucoamylase from Aspergillus awamori based on molecular dynamics simulations.

Twelve mutations were constructed to improve the thermostability of glucoamylase from Aspergillus awamori based on the results of molecular dynamics simulations. The thermal unfolding of the catalytic domain followed a putative hierarchical behavior. In addition, the unfolding of the 13 alpha-helices obeyed the random ordered mechanism, in which the alpha-helices 8, 1 and 11 unfolded more rapidly than the others. The catalytic center was well protected by the (alpha/alpha)(6)-barrel at simulation temperatures up to 600 K, whereas the catalytic base, E400, migrated from its original interior pocket to the surface of the catalytic domain by surmounting the hydrophobic barrier provided by alpha-helices 12 and 13 at 800 K. The disulfide bonds engineered to 'lock' the alpha-helix 11 on the surface of the catalytic domain dramatically increased the thermostability. Substituting G396 and G407 with Ala residues slightly increased the thermostability, whereas their specific activity and catalytic efficiency were reduced. This indicates that the introduced residues with higher hydrophobicity were favorable in the loop between alpha-helices 12 and 13, whereas they partially destroyed the hydrogen bond and salt linkage network in the catalytic center. Alpha-helices 12 and 13 can be stabilized by introducing residues with higher hydrophobicity, except for the H391M mutation.

Amino Acid Substitution↗
PubMed2000

Intermediate state during the crystal transition in aspartame, studied with thermal analysis, solid-state NMR, and molecular dynamics simulation.

Aspartame (L-alpha-aspartyl-L-phenylalanine methyl ester) is a dipeptide sweetener about 200 times as sweet as sugar. It exists in crystal forms such as IA, IB, IIA, and IIB, which differ in crystal structure and in the degree of hydration. Among these, IIA is the most stable crystal form, and its crystal structure has been well determined (Hatada et al., J. Am. Chem. Soc., 107, 4279-4282 (1985)). To elucidate the structural factors of thermal stability in the IIA form of aspartame and to examine the physical process in the crystal transformation between the IIA and IIB forms, we performed a thermal analysis and solid-state NMR measurements. We found that a quasi-stable intermediate state exists in the transformation, and it has the same crystal lattice as the usual IIA form, despite the dehydration from 1/2 mol to 1/3 mol per 1 mol of aspartame. The results of the energy component analysis and the molecular dynamics simulation suggest that the entropic effect promotes the generation of the intermediate state, which is presumably caused by the evaporation of the water of crystallization and the increase of molecular motion in aspartame. Thus, the thermal stability of the IIA form is attributable to a structural property, i.e., the crystal lattice itself is retained during the above dehydration. Moreover, the molecular dynamics simulations suggest that the aspartame molecules have two kinds of conformational flexibility in the intermediate state.

Aspartame↗
PubMed2000

Structures of scrambled disulfide forms of the potato carboxypeptidase inhibitor predicted by molecular dynamics simulations with constraints.

The structures of two species of potato carboxypeptidase inhibitor with nonnative disulfide bonds were determined by molecular dynamics simulations in explicit solvent using disulfide bond constraints that have been shown to work for the native species. Ten structures were determined; five for scrambled A (disulfide bonds between Cys8-Cys27, Cys12-Cys18, and Cys24-Cys34) and five for the scrambled C (disulfide bonds Cys8-Cys24, Cys12-Cys18, and Cys27-Cys34). The two scrambled species were both more solvent exposed than the native structure; the scrambled C species was more solvent exposed and less compact than the scrambled A species. Analysis of the loop regions indicates that certain loops in scrambled C are more nativelike than in scrambled A. These factors, combined with the fact that scrambled C has one native disulfide bond, may contribute to the observed faster conversion to the native structure from scrambled C than from scrambled A. Results from the PROCHECK program using the standard parameter database and a database specially constructed for small, disulfide-rich proteins indicate that the 10 scrambled structures have correct stereochemistry. Further, the results show that a characteristic feature of small, disulfide-rich proteins is that they score poorly using the standard PROCHECK parameter database. Proteins 2000;40:482-493.

Carboxypeptidases↗
PubMed2002

Comparison of protein solution structures refined by molecular dynamics simulation in vacuum, with a generalized Born model, and with explicit water.

The inclusion of explicit solvent water in molecular dynamics refinement of NMR structures ought to provide the most physically meaningful accounting for the effects of solvent on structure, but is computationally expensive. In order to evaluate the validity of commonly used vacuum refinements and of recently developed continuum solvent model methods, we have used three different methods to refine a set of NMR solution structures of a medium sized protein, Escherichia coli glutaredoxin 2, from starting structures calculated using the program DYANA. The three different refinement protocols used molecular dynamics simulated annealing with the program AMBER in vacuum (VAC), including a generalized Born (GB) solvent model, and a full calculation including explicit solvent water (WAT). The structures obtained using the three methods of refinements were very similar, a reflection of their generally well-determined nature. However, the structures refined with the generalized Born model were more similar to those from explicit water refinement than those refined in vacuum. Significant improvement was seen in the percentage of backbone dihedral angles in the most favored regions of phi, psi space and in hydrogen bond pattern for structures refined with the GB and WAT models, compared with the structures refined in vacuum. The explicit water calculation took an average of 200 h of CPU time per structure on an SGI cluster, compared to 15-90 h for the GB calculation (depending on the parameters used) and 2 h for the vacuum calculation. The generalized Born solvent model proved to be an excellent compromise between the vacuum and explicit water refinements, giving results comparable to those of the explicit water calculation. Some improvement for phi and psi angle distribution and hydrogen bond pattern can also be achieved by energy minimizing the vacuum structures with the GB model, which takes a much shorter time than MD simulations with the GB model.

Computer Simulation↗
PubMed1985

A molecular dynamics simulation of double-helical B-DNA including counterions and water.

We present the results of an atomic level molecular dynamical simulation of a 5-base-pair fragment of double-helical DNA with inclusion of water and sodium counterions and a complete description of their electrostatic interactions. The shape of the double helix is preserved throughout the simulation, and the helix repeat is calculated to be 10.0, in reasonable agreement with experimental results. The most flexible conformational angles in the structure are the glycosidic angle and the sugar pucker.

Computers↗
PubMed2002

Molecular dynamics simulation studies of induced fit and conformational capture in U1A-RNA binding: do molecular substates code for specificity?

Molecular dynamics (MD) simulations on stem loop 2 of U1 small nuclear RNA and a construct of the U1A protein were carried out to obtain predictions of the structures for the unbound forms in solution and to elucidate dynamical aspects of induced fit upon binding. A crystal structure of the complex between the U1A protein and stem loop 2 RNA and an NMR structure for the uncomplexed form of the U1A protein are available from Oubridge et al. (Nature, 1994, Vol. 372, pp. 432-438) and Avis et al. (Journal of Molecular Biology, 1996, Vol. 257, pp. 398-411), respectively. As a consequence, U1A-RNA binding is a particularly attractive case for investigations of induced fit in protein-nucleic acid complexation. When combined with the available structural data, the results from simulations indicate that structural adaptation of U1A protein and RNA define distinct mechanisms for induced fit. For the protein, the calculations indicate that induced fit upon binding involves a non-native thermodynamic substate in which the structure is preorganized for binding. In contrast, induced fit of the RNA involves a distortion of the native structure in solution to an unstable form. However, the RNA solution structures predicted from simulation show evidence that structures in which groups of bases are favorably oriented for binding the U1A protein are thermally accessible. These results, which quantify with computational modeling recent proposals on induced fit and conformational capture by Leuillot and Varani (Biochemistry, 2001, Vol. 40, pp. 7947-7956) and by Williamson (Nature Structural Biology, 2000, Vol. 7, pp. 834-837) suggest an important role for intrinsic molecular architecture and substates other than the native form in the specificity of protein-RNA interactions.

Computer Simulation↗
PubMed1995

Molecular dynamics simulations of alcohol dehydrogenase with a four- or five-coordinate catalytic zinc ion.

A detailed parameterization is presented of a zinc ion with one histidine and two cysteinate ligands, together with one or two water, hydroxide, aldehyde, alcohol, or alkoxide ligands. The parameterization is tailored for the active site of alcohol dehydrogenase and is obtained entirely from quantum chemical computations. The force-field reproduces excellently the geometry of quantum chemically optimized zinc complexes as well as the crystallographic geometry of the active site of alcohol dehydrogenase and small organic structures. The parameterization is used in molecular dynamics simulations and molecular mechanical energy minimizations of alcohol dehydrogenase with a four- or five-coordinate catalytic zinc ion. The active-site zinc ion seems to prefer four-coordination over five-coordination by at least 36 kJ/mol. The only stable binding site of a fifth ligand at the active-site zinc ion is opposite to the normal substrate site, in a narrow cavity behind the zinc ion. Only molecules of the size of water or smaller may occupy this site. There are large fluctuations in the geometry of the zinc coordination sphere. A four-coordinate water molecule alternates frequently (every 7 ps) between the substrate site and the fifth binding site and even two five-coordinate water molecules may interchange ligation sites without prior dissociation. Ligand exchange at the zinc ion probably proceeds by a dissociative mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗
PubMed2004

AGBNP: an analytic implicit solvent model suitable for molecular dynamics simulations and high-resolution modeling.

We have developed an implicit solvent effective potential (AGBNP) that is suitable for molecular dynamics simulations and high-resolution modeling. It is based on a novel implementation of the pairwise descreening Generalized Born model for the electrostatic component and a new nonpolar hydration free energy estimator. The nonpolar term consists of an estimator for the solute-solvent van der Waals dispersion energy designed to mimic the continuum solvent solute-solvent van der Waals interaction energy, in addition to a surface area term corresponding to the work of cavity formation. AGBNP makes use of a new parameter-free algorithm to calculate the scaling coefficients used in the pairwise descreening scheme to take into account atomic overlaps. The same algorithm is also used to calculate atomic surface areas. We show that excellent agreement is achieved for the GB self-energies and surface areas in comparison to accurate, but much more expensive, numerical evaluations. The parameter-free approach used in AGBNP and the sensitivity of the AGBNP model with respect to large and small conformational changes makes the model suitable for high-resolution modeling of protein loops and receptor sites as well as high-resolution prediction of the structure and thermodynamics of protein-ligand complexes. We present illustrative results for these kinds of benchmarks. The model is fully analytical with first derivatives and is computationally efficient. It has been incorporated into the IMPACT molecular simulation program.

Algorithms↗
PubMed2005

Adaptive resolution molecular-dynamics simulation: changing the degrees of freedom on the fly.

We present a new adaptive resolution technique for efficient particle-based multiscale molecular-dynamics simulations. The presented approach is tailor-made for molecular systems where atomistic resolution is required only in spatially localized domains whereas a lower mesoscopic level of detail is sufficient for the rest of the system. Our method allows an on-the-fly interchange between a given molecule's atomic and coarse-grained levels of description, enabling us to reach large length and time scales while spatially retaining atomistic details of the system. The new approach is tested on a model system of a liquid of tetrahedral molecules. The simulation box is divided into two regions: one containing only atomistically resolved tetrahedral molecules, and the other containing only one-particle coarse-grained spherical molecules. The molecules can freely move between the two regions while changing their level of resolution accordingly. The hybrid and the atomistically resolved systems have the same statistical properties at the same physical conditions.

Journal Article↗
PubMed2003

NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126.

PrP106-126, a peptide corresponding to residues 107-127 of the human prion protein, induces neuronal cell death by apoptosis and causes proliferation and hypertrophy of glia, reproducing the main neuropathological features of prion-related transmissible spongiform encephalopathies, such as bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. Although PrP106-126 has been shown to form amyloid-like fibrils in vitro, their structural properties have not been elucidated. Here, we investigate the conformational characteristics of a fibril-forming fragment of the mouse prion protein, MoPrP106-126, by using electron microscopy, CD spectroscopy, NMR-detected hydrogen-deuterium exchange measurements, and molecular dynamics simulations. The fibrils contain approximately 50% beta-sheet structure, and strong amide exchange protection is limited to the central portion of the peptide spanning the palindromic sequence VAGAAAAGAV. Molecular dynamics simulations indicate that MoPrP106-126 in water assumes a stable structure consisting of two four-stranded parallel beta-sheets that are tightly packed against each other by methyl-methyl interactions. Fibril formation involving polyalanine stacking is consistent with the experimental observations.

Animals↗
PubMed2006

Modeling the charge distribution at metal sites in proteins for molecular dynamics simulations.

Almost half of the proteome of living organisms is constituted of metalloproteins. Unfortunately, the ability of the current generation of molecular dynamics pairwise-additive forcefields to properly describe metal pockets is severely lacking due to the intrinsic difficulty of handling polarization and charge transfer contributions. In order to improve the description of metalloproteins, a simple reparameterization strategy is proposed herein that does not involve artificial constraints. Specifically, a non-bonded quantum mechanical-based model is used to capture the mean polarization and charge transfer contributions to the interatomic forces within the metal site. The present approach is demonstrated to provide enough accuracy to maintain the integrity of the metal pocket for a variety of metalloproteins during extended (multi-nanosecond) molecular dynamics simulations. The method enables the sampling of small conformational changes and the relaxation of local frustrations in NMR structures.

Binding Sites↗
PubMed1990

Solution structure studies of d(AC)4.d(GT)4 via restrained molecular dynamics simulations with NMR constraints derived from two-dimensional NOE and double-quantum-filtered COSY experiments.

The structure of d(AC)4.d(GT)4 is investigated by constrained molecular dynamics simulations. The constraints include proton pair distances derived from 2D NOE intensities by using the iterative relaxation matrix analysis algorithm MARDIGRAS and sugar pucker phases and amplitudes derived from double-quantum-filtered COSY spectra. Molecular dynamics runs on simulated intensity and distance sets as well as the experimental data were carried out to determine the effects of starting structure, distance constraint derivation, energy functions, and experimental errors on the end result. It was found that structural details could not be elucidated within about 1.5-A overall atomic deviation. This limitation is due in part to the accuracy of the experimental data but, more importantly, is attributable to the quantity of experimental constraints available and to imperfections in the force field utilized in the molecular dynamics calculations. Within the limits of the method, some structural characteristics of d(AC)4.d(GT)4 could be elucidated.

Computer Simulation↗
PubMed2005

IR spectra of N-methylacetamide in water predicted by combined quantum mechanical/molecular mechanical molecular dynamics simulations.

We applied the combined quantum mechanical (QM)/molecular mechanical (MM) molecular dynamics (MD) simulation method in assessing IR spectra of N-methylacetamide and its deuterated form in aqueous solutions. The model peptide is treated at the Austin Model 1 (AM1) level and the induced dipole effects by the solvent are incorporated in fluctuating solute dipole moments, which are calculated using partial charges from Mulliken population analyses without resorting to any available high-level ab initio dipole moment data. Fourier transform of the solute dipole autocorrelation function produces in silico IR spectra, in which the relative peak intensities and bandwidths of major amide bands are quantitatively compatible with experimental results only when both geometric and electronic polarizations of the peptide by the solvent are dealt with at the same quantum-mechanical level. We cast light on the importance of addressing dynamic charge fluctuations of the solute in calculating IR spectra by comparing classical and QM/MM MD simulation results. We propose the adjustable scaling factors for each amide mode to be directly compared with experimental data.

Acetamides↗
PubMed2003

The dominant interaction between peptide and urea is electrostatic in nature: a molecular dynamics simulation study.

The conformational equilibrium of a blocked valine peptide in water and aqueous urea solution is studied using molecular dynamics simulations. Pair correlation functions indicate enhanced concentration of urea near the peptide. Stronger hydrogen bonding of urea-peptide compared to water-peptide is observed with preference for helical conformation. The potential of mean force, computed using umbrella sampling, shows only small differences between urea and water solvation that are difficult to quantify. The changes in solvent structure around the peptide are explained by favorable electrostatic interactions (hydrogen bonds) of urea with the peptide backbone. There is no evidence for significant changes in hydrophobic interactions in the two conformations of the peptide in urea solution. Our simulations suggest that urea denatures proteins by preferentially forming hydrogen bonds to the peptide backbone, reducing the barrier for exposing protein residues to the solvent, and reaching the unfolded state.

Computer Simulation↗
PubMed2005

Ab initio molecular dynamics simulations of beta-D-glucose and beta-D-xylose degradation mechanisms in acidic aqueous solution.

Ab initio molecular dynamics simulations were employed to investigate, with explicit solvent water molecules, beta-D-glucose and beta-D-xylose degradation mechanisms in acidic media. The rate-limiting step in sugar degradation was found to be protonation of the hydroxyl groups on the sugar ring. We found that the structure of water molecules plays a significant role in the acidic sugar degradation pathways. Firstly, a water molecule competes with the hydroxyl group on the sugar ring for protons. Secondly, water forms hydrogen bonds with the hydroxyl groups on the sugar rings, thus weakening the C-C and C-O bonds (each to a different degree). Note that the reaction pathways could be altered due to the change of relative stability of the C-C and C-O bonds. Thirdly, water molecules that are hydrogen-bonded to sugar hydroxyls could easily extract a proton from the reaction intermediate, terminating the reaction. Indeed, the sugar degradation pathway is complex due to multiple protonation probabilities and the surrounding water structure. Our experimental data support multiple sugar acidic degradation pathways.

Computer Simulation↗