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.

Variable selection algorithm for the construction of MIMO operating point dependent neurofuzzy networks

An input variable selection procedure is introduced for the identification and construction of multi-input multi-output (MIMO) neurofuzzy operating point dependent models. The algorithm is an extension of a forward modified Gram-Schmidt orthogonal least squares procedure for a linear model structure which is modified to accommodate nonlinear system modeling by incorporating piecewise locally linear model fitting. The proposed input nodes selection procedure effectively tackles the problem of the curse of dimensionality associated with lattice-based modeling algorithms such as radial basis function neurofuzzy networks, enabling the resulting neurofuzzy operating point dependent model to be widely applied in control and estimation. Some numerical examples are given to demonstrate the effectiveness of the proposed construction algorithm.

Controlling steering and judging heading: retinal flow, visual direction, and extraretinal information

The contribution of retinal flow (RF), extraretinal (ER), and egocentric visual direction (VD) information in locomotor control was explored. First, the recovery of heading from RF was examined when ER information was manipulated; results confirmed that ER signals affect heading judgments. Then the task was translated to steering curved paths, and the availability and veracity of VD were manipulated with either degraded or systematically biased RE Large steering errors resulted from selective manipulation of RF and VD, providing strong evidence for the combination of RF, ER, and VD. The relative weighting applied to RF and VD was estimated. A point-attractor model is proposed that combines redundant sources of information for robust locomotor control with flexible trajectory planning through active gaze.

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.

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.

Syntheses, spectroelectrochemical studies, and molecular and electronic structures of ferrocenyl ene-diynes

The readily available complex 1,1-dibromo-2-ferrocenylethylene provides a convenient entry point for the preparation of a wide range of cross-conjugated 1,1-bis(alkynyl)-2-ferrocenylethenes through simple Pd(0)/Cu(I)-mediated cross-coupling reactions with 1-alkynes. The ferrocene moiety in compounds of the general form FcCHC(CCR)2 is essentially electronically isolated from the cross-conjugated π system, as evidenced by IR and UV−vis spectroelectrochemical experiments and quantum chemical calculations. In contrast to the other examples which give stable ferrocenium derivatives upon electrochemical oxidation, the aniline derivatives [FcCHC(CCC6H4NH2-4)2]+ and [FcCHC(CCC6H4NMe2-4)2]+ proved to be unstable on the time scale of the spectroelectrochemical experiments, leading to passivation of the electrode surface over time. There is no significant thermodynamic stabilization of the radical anion [FcCHC(CCC6H4NO2-4)2]− relative to the neutral and dianionic analogues, although the dianion [FcCHC(CCC6H4NO2- 4)2]2− could be studied as a relatively chemically stable species and is well described in terms of two linked nitrophenyl radicals. The capacity to introduce a relatively isolated point charge at the periphery of the cross-conjugated π system appears to make these complexes useful templates for the construction of electrochemically gated quantum interference transistors.

Many-body effect in electrorheological responses

The many-body effect in the kinetic responses of ER fluids is studied by a molecular-dynamic simulation method. The mutual polarization effects of the particles are considered by self-consistently calculating the dipole strength on each particle according to the external field and the dipole field due to all the other particles in the fluids. The many-body effect is found to increase with the enhancement of the particle concentration and the permittivity ratio between the solvent and the particles. The calculated response times are shorter than that predicted with the 'point-dipole' model and agree very well with experimental results. The many-body effect enhances the shear stresses of the fluids by several times. But they are not proportional to the many-body correction factor lambda as expected. This is due to the fact that larger interaction forces between the particles lead to coarsening of the fibers formed in the suspensions. The results show that the many-body and multipolar interaction between the particles must be treated comprehensively in the simulations in order to get more reliable results.

A moving point approach to model shallow ice sheets: a study case with radially-symmetrical ice sheets

Predicting the evolution of ice sheets requires numerical models able to accurately track the migration of ice sheet continental margins or grounding lines. We introduce a physically based moving point approach for the flow of ice sheets based on the conservation of local masses. This allows the ice sheet margins to be tracked explicitly and the waiting time behaviours to be modelled efficiently. A finite difference moving point scheme is derived and applied in a simplified context (continental radially-symmetrical shallow ice approximation). The scheme, which is inexpensive, is validated by comparing the results with moving-margin exact solutions and steady states. In both cases the scheme is able to track the position of the ice sheet margin with high precision.

A moving-point approach to model shallow ice sheets: a study case with radially symmetrical ice sheets

Predicting the evolution of ice sheets requires numerical models able to accurately track the migration of ice sheet continental margins or grounding lines. We introduce a physically based moving-point approach for the flow of ice sheets based on the conservation of local masses. This allows the ice sheet margins to be tracked explicitly. Our approach is also well suited to capture waiting-time behaviour efficiently. A finite-difference moving-point scheme is derived and applied in a simplified context (continental radially symmetrical shallow ice approximation). The scheme, which is inexpensive, is verified by comparing the results with steady states obtained from an analytic solution and with exact moving-margin transient solutions. In both cases the scheme is able to track the position of the ice sheet margin with high accuracy.

The counter-propagating Rossby-wave perspective on baroclinic instability. II: Application to the Charney model

The constant-density Charney model describes the simplest unstable basic state with a planetary-vorticity gradient, which is uniform and positive, and baroclinicity that is manifest as a negative contribution to the potential-vorticity (PV) gradient at the ground and positive vertical wind shear. Together, these ingredients satisfy the necessary conditions for baroclinic instability. In Part I it was shown how baroclinic growth on a general zonal basic state can be viewed as the interaction of pairs of ‘counter-propagating Rossby waves’ (CRWs) that can be constructed from a growing normal mode and its decaying complex conjugate. In this paper the normal-mode solutions for the Charney model are studied from the CRW perspective. Clear parallels can be drawn between the most unstable modes of the Charney model and the Eady model, in which the CRWs can be derived independently of the normal modes. However, the dispersion curves for the two models are very different; the Eady model has a short-wave cut-off, while the Charney model is unstable at short wavelengths. Beyond its maximum growth rate the Charney model has a neutral point at finite wavelength (r=1). Thereafter follows a succession of unstable branches, each with weaker growth than the last, separated by neutral points at integer r—the so-called ‘Green branches’. A separate branch of westward-propagating neutral modes also originates from each neutral point. By approximating the lower CRW as a Rossby edge wave and the upper CRW structure as a single PV peak with a spread proportional to the Rossby scale height, the main features of the ‘Charney branch’ (0model where the positive PV gradient exists only at the tropopause

Uncertainty assessment of a process-based integrated catchment model of phosphorus

Despite the many models developed for phosphorus concentration prediction at differing spatial and temporal scales, there has been little effort to quantify uncertainty in their predictions. Model prediction uncertainty quantification is desirable, for informed decision-making in river-systems management. An uncertainty analysis of the process-based model, integrated catchment model of phosphorus (INCA-P), within the generalised likelihood uncertainty estimation (GLUE) framework is presented. The framework is applied to the Lugg catchment (1,077 km2), a River Wye tributary, on the England–Wales border. Daily discharge and monthly phosphorus (total reactive and total), for a limited number of reaches, are used to initially assess uncertainty and sensitivity of 44 model parameters, identified as being most important for discharge and phosphorus predictions. This study demonstrates that parameter homogeneity assumptions (spatial heterogeneity is treated as land use type fractional areas) can achieve higher model fits, than a previous expertly calibrated parameter set. The model is capable of reproducing the hydrology, but a threshold Nash-Sutcliffe co-efficient of determination (E or R 2) of 0.3 is not achieved when simulating observed total phosphorus (TP) data in the upland reaches or total reactive phosphorus (TRP) in any reach. Despite this, the model reproduces the general dynamics of TP and TRP, in point source dominated lower reaches. This paper discusses why this application of INCA-P fails to find any parameter sets, which simultaneously describe all observed data acceptably. The discussion focuses on uncertainty of readily available input data, and whether such process-based models should be used when there isn’t sufficient data to support the many parameters.

Strategic management of non-point source pollution from sewage sludge

In the UK, the recycling of sewage sludge to land is expected to double by 2006 but the security of this route is threatened by environmental concerns and health scares. Strategic investment is needed to ensure sustainable and secure sludge recycling outlets. At present, the security of this landbank for sludge recycling is determined by legislation relating to nutrient rather than potentially toxic elements (PTEs) applications to land - especially the environmental risk linked to soil phosphorus (P) saturation. We believe that not all land has an equal risk of contributing nutrients derived from applications to land to receiving waters. We are currently investigating whether it is possible to minimise nutrient loss by applying sludge to land outside Critical Source Areas (CSAs) regardless of soil P Index status. Research is underway to develop a predictive and spatially-sensitive, semi-distributed model of critical thresholds for sludge application that goes beyond traditional 'end-of-pipe" or "edge-of-field" modelling, to include hydrological flow paths and delivery mechanisms to receiving waters from non-point sources at the catchment scale.

Evaluating the risk of non-point source pollution from biosolids: integrated modelling of nutrient losses at field and catchment scales

A semi-distributed model, INCA, has been developed to determine the fate and distribution of nutrients in terrestrial and aquatic systems. The model simulates nitrogen and phosphorus processes in soils, groundwaters and river systems and can be applied in a semi-distributed manner at a range of scales. In this study, the model has been applied at field to sub-catchment to whole catchment scale to evaluate the behaviour of biosolid-derived losses of P in agricultural systems. It is shown that process-based models such as INCA, applied at a wide range of scales, reproduce field and catchment behaviour satisfactorily. The INCA model can also be used to generate generic information for risk assessment. By adjusting three key variables: biosolid application rates, the hydrological connectivity of the catchment and the initial P-status of the soils within the model, a matrix of P loss rates can be generated to evaluate the behaviour of the model and, hence, of the catchment system. The results, which indicate the sensitivity of the catchment to flow paths, to application rates and to initial soil conditions, have been incorporated into a Nutrient Export Risk Matrix (NERM).