Computer simulations of structures, energetics and dynamics of myoglobin center dot center dot center dot ligand complexes

Myoglobin has been studied in considerable detail using different experimental and computational techniques over the past decades. Recent developments in time-resolved spectroscopy have provided experimental data amenable to detailed atomistic simulations. The main theme of the present review are results on the structures, energetics and dynamics of ligands ( CO, NO) interacting with myoglobin from computer simulations. Modern computational methods including free energy simulations, mixed quantum mechanics/molecular mechanics simulations, and reactive molecular dynamics simulations provide insight into the dynamics of ligand dynamics in confined spaces complementary to experiment. Application of these methods to calculate and understand experimental observations for myoglobin interacting with CO and NO are presented and discussed.

Studying reactive processes with classical dynamics: rebinding dynamics in MbNO

A new surface-crossing algorithm suitable for describing bond-breaking and bond-forming processes in molecular dynamics simulations is presented. The method is formulated for two intersecting potential energy manifolds which dissociate to different adiabatic states. During simulations, crossings are detected by monitoring an energy criterion. If fulfilled, the two manifolds are mixed over a finite number of time steps, after which the system is propagated on the second adiabat and the crossing is carried out with probability one. The algorithm is extensively tested (almost 0.5 mu s of total simulation time) for the rebinding of NO to myoglobin. The unbound surface ((FeNO)-N-...) is represented using a standard force field, whereas the bound surface (Fe-NO) is described by an ab initio potential energy surface. The rebinding is found to be nonexponential in time, in agreement with experimental studies, and can be described using two time constants. Depending on the asymptotic energy separation between the manifolds, the short rebinding timescale is between 1 and 9 ps, whereas the longer timescale is about an order of magnitude larger. NO molecules which do not rebind within 1 ns are typically found in the Xenon-4 pocket, indicating the high affinity of NO to this region in the protein.

Computational chemistry for elucidating protein function: energetics and dynamics of myoglobin-ligand systems

State-of-the-art computational methodologies are used to investigate the energetics and dynamics of photodissociated CO and NO in myoglobin (Mb···CO and Mb···NO). This includes the combination of molecular dynamics, ab initio MD, free energy sampling, and effective dynamics methods to compare the results with studies using X-ray crystallography and ultrafast spectroscopy metho ds. It is shown that modern simulation techniques along with careful description of the intermolecular interactions can give quantitative agreement with experiments on complex molecular systems. Based on this agreement predictions for as yet uncharacterized species can be made.

Ligand dynamics in myoglobin: calculation of infrared spectra for photodissociated NO

We present molecular dynamics simulations of the photodissociated state of MbNO performed at 300 K using a fluctuating charge model for the nitric oxide (NO) ligand. After dissociation, NO is observed to remain mainly in the centre of the distal haem pocket, although some movement towards the primary docking site and the xenon-4 pocket can be seen. We calculate the NO infrared spectrum for the photodissociated ligand within the haem pocket and find a narrow peak in the range 1915-1922 cm(-1). The resulting blue shift of 1 to 8 cm(-1) compared to gas-phase NO is much smaller than the red shifts calculated and observed for carbon monoxide (CO) in Mb. A small splitting, due to NO in the xenon-4 pocket, is also observed. At lower temperatures, the spectra and conformational space explored by the ligand remain largely unchanged, but the electrostatic interactions with residue His64 become increasingly significant in determining the details of the ligand orientation within the distal haem pocket. The investigation of the effect of the L29F mutation reveals significant differences between the behaviour of NO and that of CO, and suggests a coupling between the ligand and the protein dynamics due to the different ligand dipole moments.

Theoretical investigation of infrared spectra and pocket dynamics of photodissociated carbonmonoxy myoglobin

Molecular dynamics simulations of the photodissociated state of carbonmonoxy myoglobin (MbCO) are presented using a fluctuating charge model for CO. A new three-point charge model is fitted to high-level ab initio calculations of the dipole and quadrupole moment functions taken from the literature. The infrared spectrum of the CO molecule in the heme pocket is calculated using the dipole moment time autocorrelation function and shows good agreement with experiment. In particular, the new model reproduces the experimentally observed splitting of the CO absorption spectrum. The splitting of 3–7 cm−1 (compared to the experimental value of 10 cm−1) can be directly attributed to the two possible orientations of CO within the docking site at the edge of the distal heme pocket (the B states), as previously suggested on the basis of experimental femtosecond time-resolved infrared studies. Further information on the time evolution of the position and orientation of the CO molecule is obtained and analyzed. The calculated difference in the free energy between the two possible orientations (Fe···CO and Fe···OC) is 0.3 kcal mol−1 and agrees well with the experimentally estimated value of 0.29 kcal mol−1. A comparison of the new fluctuating charge model with an established fixed charge model reveals some differences that may be critical for the correct prediction of the infrared spectrum and energy barriers. The photodissociation of CO from the myoglobin mutant L29F using the new model shows rapid escape of CO from the distal heme pocket, in good agreement with recent experimental data. The effect of the protein environment on the multipole moments of the CO ligand is investigated and taken into account in a refined model. Molecular dynamics simulations with this refined model are in agreement with the calculations based on the gas-phase model. However, it is demonstrated that even small changes in the electrostatics of CO alter the details of the dynamics.

Modeling entangled dynamics: comparison between stochastic single-chain and multichain models

To test the effectiveness of stochastic single-chain models in describing the dynamics of entangled polymers, we systematically compare one such model; the slip-spring model; to a multichain model solved using stochastic molecular dynamics(MD) simulations (the Kremer-Grest model). The comparison involves investigating if the single-chain model can adequately describe both a microscopic dynamical and a macroscopic rheological quantity for a range of chain lengths. Choosing a particular chain length in the slip-spring model, the parameter values that best reproduce the mean-square displacement of a group of monomers is determined by fitting toMDdata. Using the same set of parameters we then test if the predictions of the mean-square displacements for other chain lengths agree with the MD calculations. We followed this by a comparison of the time dependent stress relaxation moduli obtained from the two models for a range of chain lengths. After identifying a limitation of the original slip-spring model in describing the static structure of the polymer chain as seen in MD, we remedy this by introducing a pairwise repulsive potential between the monomers in the chains. Poor agreement of the mean-square monomer displacements at short times can be rectified by the use of generalized Langevin equations for the dynamics and resulted in significantly improved agreement.

Temperature dependence of protein dynamics simulated with three different water models

The effect of variation of the water model on the temperature dependence of protein and hydration water dynamics is examined by performing molecular dynamics simulations of myoglobin with the TIP3P, TIP4P, and TIP5P water models and the CHARMM protein force field at temperatures between 20 and 300 K. The atomic mean-square displacements, solvent reorientational relaxation times, pair angular correlations between surface water molecules, and time-averaged structures of the protein are all found to be similar, and the protein dynamical transition is described almost indistinguishably for the three water potentials. The results provide evidence that for some purposes changing the water model in protein simulations without a loss of accuracy may be possible.

Molecular modelling studies of binding of DACD derivatives into G-Quadruplex DNA: comparison of force field and quantum polarized ligand docking methods

The DNA G-qadruplexes are one of the targets being actively explored for anti-cancer therapy by inhibiting them through small molecules. This computational study was conducted to predict the binding strengths and orientations of a set of novel dimethyl-amino-ethyl-acridine (DACA) analogues that are designed and synthesized in our laboratory, but did not diffract in Synchrotron light.Thecrystal structure of DNA G-Quadruplex(TGGGGT)4(PDB: 1O0K) was used as target for their binding properties in our studies.We used both the force field (FF) and QM/MM derived atomic charge schemes simultaneously for comparing the predictions of drug binding modes and their energetics. This study evaluates the comparative performance of fixed point charge based Glide XP docking and the quantum polarized ligand docking schemes. These results will provide insights on the effects of including or ignoring the drug-receptor interfacial polarization events in molecular docking simulations, which in turn, will aid the rational selection of computational methods at different levels of theory in future drug design programs. Plenty of molecular modelling tools and methods currently exist for modelling drug-receptor or protein-protein, or DNA-protein interactionssat different levels of complexities.Yet, the capasity of such tools to describevarious physico-chemical propertiesmore accuratelyis the next step ahead in currentresearch.Especially, the usage of most accurate methods in quantum mechanics(QM) is severely restricted by theirtedious nature. Though the usage of massively parallel super computing environments resulted in a tremendous improvement in molecular mechanics (MM) calculations like molecular dynamics,they are still capable of dealing with only a couple of tens to hundreds of atoms for QM methods. One such efficient strategy that utilizes thepowers of both MM and QM are the QM/MM hybrid methods. Lately, attempts have been directed towards the goal of deploying several different QM methods for betterment of force field based simulations, but with practical restrictions in place. One of such methods utilizes the inclusion of charge polarization events at the drug-receptor interface, that is not explicitly present in the MM FF.

Segmental dynamics in entangled linear polymer melts

We present molecular dynamics (MD) and slip-springs model simulations of the chain segmental dynamics in entangled linear polymer melts. The time-dependent behavior of the segmental orientation autocorrelation functions and mean-square segmental displacements are analyzed for both flexible and semiflexible chains, with particular attention paid to the scaling relations among these dynamic quantities. Effective combination of the two simulation methods at different coarse-graining levels allows us to explore the chain dynamics for chain lengths ranging from Z ≈ 2 to 90 entanglements. For a given chain length of Z ≈ 15, the time scales accessed span for more than 10 decades, covering all of the interesting relaxation regimes. The obtained time dependence of the monomer mean square displacements, g1(t), is in good agreement with the tube theory predictions. Results on the first- and second-order segmental orientation autocorrelation functions, C1(t) and C2(t), demonstrate a clear power law relationship of C2(t) C1(t)m with m = 3, 2, and 1 in the initial, free Rouse, and entangled (constrained Rouse) regimes, respectively. The return-to-origin hypothesis, which leads to inverse proportionality between the segmental orientation autocorrelation functions and g1(t) in the entangled regime, is convincingly verified by the simulation result of C1(t) g1(t)−1 t–1/4 in the constrained Rouse regime, where for well-entangled chains both C1(t) and g1(t) are rather insensitive to the constraint release effects. However, the second-order correlation function, C2(t), shows much stronger sensitivity to the constraint release effects and experiences a protracted crossover from the free Rouse to entangled regime. This crossover region extends for at least one decade in time longer than that of C1(t). The predicted time scaling behavior of C2(t) t–1/4 is observed in slip-springs simulations only at chain length of 90 entanglements, whereas shorter chains show higher scaling exponents. The reported simulation work can be applied to understand the observations of the NMR experiments.

GSHMC: an efficient method for molecular simulation

The hybrid Monte Carlo (HMC) method is a popular and rigorous method for sampling from a canonical ensemble. The HMC method is based on classical molecular dynamics simulations combined with a Metropolis acceptance criterion and a momentum resampling step. While the HMC method completely resamples the momentum after each Monte Carlo step, the generalized hybrid Monte Carlo (GHMC) method can be implemented with a partial momentum refreshment step. This property seems desirable for keeping some of the dynamic information throughout the sampling process similar to stochastic Langevin and Brownian dynamics simulations. It is, however, ultimate to the success of the GHMC method that the rejection rate in the molecular dynamics part is kept at a minimum. Otherwise an undesirable Zitterbewegung in the Monte Carlo samples is observed. In this paper, we describe a method to achieve very low rejection rates by using a modified energy, which is preserved to high-order along molecular dynamics trajectories. The modified energy is based on backward error results for symplectic time-stepping methods. The proposed generalized shadow hybrid Monte Carlo (GSHMC) method is applicable to NVT as well as NPT ensemble simulations.

Molecular insights into aggregates made of amphiphilic Fmoc-tetrapeptides

Pre-assembled aggregates made of Fmoc-conjugated RGDS and GRDS peptides, where Fmoc refers to fluorenylmethoxycarbonyl, have been investigated using atomistic molecular dynamics simulations. The structural characteristics of twelve different models involving two sheets packed with the Fmoc-aligned or with the charged side groups oriented face-to-face, each one containing seven explicit peptide molecules arranged in parallel or antiparallel, have been evaluated for each Fmoc-tetrapeptide. Structural criteria have been used to select the preferred assembly for each Fmoc-tetrapeptide. The two peptides have been found to prefer b-sheet assemblies with a parallel configuration under simulated low concentration conditions. Furthermore, the assembly is dominated by the interactions among Fmoc units. The overall results provide a complete atomistic view of the interactions between Fmoc-peptide molecules comprised within the same sheet or in different sheets that was not achieved experimentally.

A Multitechnique Study of Structure and Dynamics of Polyfluorene Cast Films and the Influence on Their Photoluminescence

This article describes the microstructure and dynamics in the solid state of polyfluorene-based polymers, poly(9,)-dioctylfluorenyl-2,7-diyl) (PFO), a semicrystalline polymer, and poly [(9,9-dioctyl- 2,7-divinylene-fluorenylene)-alt-co-{2-methoxy-5-(2-ethyl-hexyloxy)- 1,4-phenylene vinylene}, a copolymer with mesomorphic phase properties. These Structures were determined by wide-angle X-ray scattering (WAXS) measurements, Assuming a packing model for the copolymer structure, where the planes of the phenyl rings are stacked and separated by an average distance of similar to 4.5 angstrom and laterally spaced by about similar to 16 angstrom, we followed the evolution of these distances as a function of temperature using WAXS and associated the changes observed to the polymer relaxation processes identified by dynamical mechanical thermal analysis. Specific molecular motions were studied by solid-state nuclear magnetic resonance. The onset of the side-chain motion at about 213 K (beta-relaxation) produced a small increase in the lateral spacing and in the stacking distance of the phenyl rings in them aggregated Structures, Besides, at about 383 K (alpha-relaxation) there occurs a significant increase in the amplitude of the torsion motion in the backbone, producing a greater increase in the stacking distance of the phenyl rings. Similar results were observed in the semicrystalline phase of PFO, but in this case the presence of the crystalline structure affects considerably the overall dynamics, which tends to be more hindered. Put together, Our data explain many features of the temperature dependence of the photoluminescence of these two polymers.

Host-guest system of 4-nerolidylcatechol in 2-hydroxypropyl-beta-cyclodextrin: preparation, characterization and molecular modeling

The interaction of 4-nerolidylcatechol (4-NRC), a potent antioxidant agent, and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was investigated by the solubility method using Fourier transform infrared (FTIR) methods in addition to UV-Vis, (1)H-nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. The inclusion complexes were prepared using grinding, kneading and freeze-drying methods. According to phase solubility studies in water a B(S)-type diagram was found, displaying a stoichiometry complexation of 2:1 (drug:host) and stability constant of 6494 +/- A 837 M(-1). Stoichiometry was established by the UV spectrophotometer using Job`s plot method and, also confirmed by molecular modeling. Data from (1)H-NMR, and FTIR, experiments also provided formation evidence of an inclusion complex between 4-NRC and HP-beta-CD. 4-NRC complexation indeed led to higher drug solubility and stability which could probably be useful to improve its biological properties and make it available to oral administration and topical formulations.

Defeitos pontuais nos compostos intermetálicos ZrNi e Zr/sub 2/Ni estudados por dinâmica molecular

Empregamos a técnica de Dinâmica Molecular para estudar propriedades de defeitos pontuais nos compostos intermetálicos ZrNi e Zr2Ni. Descrevemos as configurações estáveis de defeitos e mecanismos de migração, assim como as energias envolvidas. Os potenciais interatômicos foram derivados do Embedded Atom Model. No intuito de levar em conta a variação de estequiometria causada pela presença de alguns tipos de defeitos em intermetálicos, apresentamos um método numérico que fornece a energia efetiva de formação de defeitos e aplicamos o método ao ZrNi e Zr2Ni. Os resultados mostraram que vacâncias são mais estáveis na sub—rede do Ni, com energia de formação de 0,83 e-0,61 eV em ZrNi e Zr2Ni, respectivamente. Vacâncias de Zr são instáveis em ambos compostos; elas decaem espontaneamente em pares anti—sítio e vacância de Ni. Configurações e energias de formação de intersticiais também foram calculadas e mostraram comportamentos similares. Em ZrNi, a migração de vacâncias ocorre preferencialmente nas direções [025] e [100], com as respectivas energias de migração 0,67 e 0,73 eV, e é um processo essencialmente bidimensional no plano (001). Em Zr,Ni, a migração de vacâncias é unidimensional, ocorrendo na direção [001], com energia de migração de 0,67 eV. Em ambos compostos a presença de defeitos de anti—sítio de Ni diminui a energia de migração da vacância de Ni em até 3 vezes e facilita a movimentação em três dimensões. Mecanismos de anel não são energeticamente eficientes em comparação com saltos diretos. As configurações estáveis de intersticiais em ambos compostos consistem em um átomo de Ni sobre o plano (001) entre dois vizinhos de Zr fora do plano. Intersticiais de Zr são instáveis e tendem a deslocar um átomo de Ni, ocupando seu sítio. Energias de deslocamento foram estudadas através de simulações de irradiação de ambos compostos. Durante o processo de colisão binária, um potencial universal ZBL foi usado para colisões a curta distância. Para distâncias intermediárias usamos um potencial de união arbitrário. Zr mostrou—se mais difícil de ser arrancado de seu sítio do que Ni. Encontramos valores de energia de deslocamento no intervalo de aproximadamente 29 eV até 546 eV. Alguns resultados experimentais são mostrados e apresentam boa concordância com os cálculos.

Host-guest system of 4-nerolidylcatechol in 2-hydroxypropyl-beta-cyclodextrin: preparation, characterization and molecular modeling

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)