Water molecules in DNA recognition II: a molecular dynamics view of the structure and hydration of the trp operator

The structure and hydration of the DNA duplex d-(AGCGTACTAGTACGCT)2 corresponding to the trp operator fragment used in the crystal structure of the half site complex (PDB entry 1TRR) was studied by a 1.4 ns molecular dynamics simulation in water. The simulation, starting from a B-DNA conformation, used a non-bonded cutoff of 1.4 nm with a reaction field correction and resulted in a stable trajectory. The average DNA conformation obtained was closer to the ones found in the crystal structures of the complexes (PDB entries 1TRO and 1TRR) than to the crystal structure of unbound trp operator (Nucleic Acid Database entry BDJ061). The DNA hydration was characterized in terms of hydrogen bond percentages and corresponding residence times. The residence times of water molecules within 0.35 nm of the DNA non-exchangeable protons were calculated for comparison with NMR measurements of intermolecular water-DNA NOEs and nuclear magnetic relaxation dispersion measurements. No significant difference was found between major and minor groove hydration. The DNA donors and acceptors were hydrogen bonded to water molecules for 77(+/-19)% of the time on average. The average residence time of the hydrogen bonded water molecules was 11(+/-11) ps with a maximum of 223 ps. When all water molecules within NOE distance (0.35 nm) of non-exchangeable protons were considered, the average residence times increased to an average of 100(+/-4) ps and a maximum of 608 ps. These results agree with the experimental NMR results of Sunnerhagen et al. which did not show any evidence for water molecules bound with more than 1 ns residence time on the DNA surface. The exchange of hydration water from the DNA occurred in the major groove primarily through direct exchange with the bulk solvent, while access to and from the minor groove frequently proceeded via pathways involving ribose O3' and O4' and phosphate O2P oxygen atoms. The most common water diffusion pathways in the minor groove were perpendicular to the groove direction. In general, water molecules visited only a limited number of sites in the DNA grooves before exiting. The hydrogen bonding sites, where hydrogen bonds could be formed with donor and acceptor groups of the DNA, were filled with water molecules with an average B-factor value of 0.58 mn2. No special values were observed at any of the sites, where water molecules were observed both in the trp repressor/operator co-crystals and in the crystal structure of unbound DNA.     

Application of molecular dynamics and free energy perturbation methods to metalloporphyrin-ligand systems II: CO and dioxygen binding to myoglobin

The protein contribution to the relative binding affinity of the ligands CO and O2 toward myoglobin (Mb) has been simulated using free energy perturbation calculations. The tautomers of the His E7 residue are different for the oxymyoglobin (MbO2) and carboxymyoglobin (MbCO) systems. This was modeled by performing two-step calculations that mutate the ligand and mutate the His E7 tautomers in separate steps. Differences in hydrogen bonding to the O2 and CO ligands were incorporated into the model. The O2 complex was calculated to be 2-3 kcal/mol more stable than the corresponding CO complex when compared to the same difference in an isolated heme control. This value agrees well with the experimental value of 2.0 kcal/mol. In qualitative agreement with experiments, the Fe-C-O bond is found to be bent (theta = 159.8 degrees) with a small tilt (theta = 6.2 degrees). The contributions made by each of the 29 residues--within the 9.0-A radius of the iron atom--to the free energy difference are separated into van der Waals and electrostatic contributions; the latter contributions are dominant. Aside from the proximal histidine and the heme group, the residues having the largest difference in free energy in mutating MbO2-->MbCO are His E7, Phe CD1, Phe CD4, Val E11, and Thr E10.     

Deducing polymeric structure from aqueous molecular dynamics simulations of oligosaccharides: predictions from simulations of hyaluronan tetrasaccharides compared with hydrodynamic and X-ray fibre diffraction data

Molecular dynamics simulations of the two hyaluronan tetrasaccharides in water predict that over a period of 500 ps, their central linkages populate a single primary minima. Over the same period the peripheral linkages explore this minima, but also a secondary minima. Structures constructed using the primary minima were found to be extended left-handed helices of axial rise per disaccharide (h) 0.8 to 1.0 nm and 2.8 to 4.5 disaccharides per turn (n), in good agreement with n=3 and n=4 helices found by X-ray fibre diffraction studies. We have used the predicted average conformation from molecular dynamics to calculate the translational diffusion coefficients of the oligosaccharide series up to decasaccharide, and compared these with experimental measurements obtained using the method of capillary dispersion. Our calculated values are found to be in good agreement with experiment beyond the size of a tetrasaccharide. A partial digest of hyaluronan in the molecular mass range 10 to 100 kDa was fractionated by gel chromatography. Molecular weights were determined by in-line laser light-scattering measurements, and the translational diffusion coefficients of selected fractions were determined by dynamic laser light-scattering. A similar experiment was performed on hyaluronan with a molecular mass greater than 1MDa. The data suggest a change from rod-like to stiff coil behaviour beyond a molecular weight of 10 kDa. We have also examined the conformations available using the secondary minima, found at the peripheral linkages. In contrast to the extended structures previously described we have found left and right-handed helices with high values of n (5-10) and low values of h. Although there is no experimental evidence for these structures, they are of interest as, over short stretches, they would introduce folds, loops, and turns into the hyaluronan molecule. Such shapes may play an important role in the hydrodynamics of hyaluronan and its interaction with lipids and proteins.     

A model of synchronization of motor acts to a stimulus sequence. II. Stability analysis, error estimation and simulations

In Part I (Mates 1994), a linear model of timing and error-corrections was constructed that aims at an explanation of the mechanisms underlying a subject's performance in an experimental paradigm, in which the task is to synchronize a sequence of motor acts to a sequence of stimuli. The model consists of two error-corrective mechanisms: (1) corrections of period (inverted frequency) of the sequence of responses; (2) corrections of phase shift of that sequence (synchronization error). In this paper, the influence of the physiologically justifiable model variables and of initial conditions on the steady-state response sequence as well as the stability of performance of the model are analyzed. The model is stable for error-correction gains in the range from 0 to 2. Comparison with known empirical data supports the assumption that reasonable values are less than 1. Furthermore, an alternative to the basic linear model is introduced in which the possible character of the process of subjective acquisition of the synchronization error is discussed. On the basis of findings from other experimental paradigms (fusion and order threshold) it can be assumed that the subjective estimate is a nonlinear function of the difference between the temporal central availability of internal representations of the stimulus and response-feedback events. Some other known synchronization data are simulated by the nonlinear modification of the model in this paper. A good fit of the simulation results achieved further justifies the model structure proposed. Finally, the possible effect of the subjective synchronization-error estimation on empirical data is discussed.     

Monte Carlo simulations of protein folding. II. Application to protein A, ROP, and crambin

The hierarchy of lattice Monte Carlo models described in the accompanying paper (Kolinski, A., Skolnick, J. Monte Carlo simulations of protein folding. I. Lattice model and interaction scheme. Proteins 18:338-352, 1994) is applied to the simulation of protein folding and the prediction of 3-dimensional structure. Using sequence information alone, three proteins have been successfully folded: the B domain of staphylococcal protein A, a 120 residue, monomeric version of ROP dimer, and crambin. Starting from a random expanded conformation, the model proteins fold along relatively well-defined folding pathways. These involve a collection of early intermediates, which are followed by the final (and rate-determining) transition from compact intermediates closely resembling the molten globule state to the native-like state. The predicted structures are rather unique, with native-like packing of the side chains. The accuracy of the predicted native conformations is better than those obtained in previous folding simulations. The best (but by no means atypical) folds of protein A have a coordinate rms of 2.25 A from the native C alpha trace, and the best coordinate rms from crambin is 3.18 A. For ROP monomer, the lowest coordinate rms from equivalent C alpha s of ROP dimer is 3.65 A. Thus, for two simple helical proteins and a small alpha/beta protein, the ability to predict protein structure from sequence has been demonstrated.     

Neighbourhood density effects in reading aloud: New insights from simulations with the DRC model.

A series of nine simulations with the Dual Route Cascaded (DRC) model (M. Coltheart, K. Rastle, C. Perry, R. Langdon, & J. Ziegler, 2001) investigated neighbourhood density (N) effects in nonword and word naming. Two main findings emerged from this work. First, when naming nonwords there are two loci for the effect of N in the model, contrary to M. Coltheart et al.'s single locus explanation of what the model is doing. The early N effect involves interactive activation between the orthographic lexicon and the letter units such that high N facilitates letter identification, which in turn affects the nonlexical route. The late N effect arises from activation in the orthographic lexicon that feeds forward to the phonological lexicon and primes phonemes in the phoneme system. Second, when naming words the presence/absence of an effect of N on the Letter Units through feedback from the lexical level depends on the parameter settings. Implications and suggestions for future directions are made. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Leadership dynamics: Character and character structure in executives.

While the public and the mass media have continued to uphold and find relevance in the time-honored construct of character, the scientific and professional community are in the process of rediscovering a construct they had essentially relinquished for the past few decades. This paper briefly traces the recent history of character and character structure in psychology and overviews a number of promising theoretical and empirical studies of character and character structure that have particular relevance for consulting psychologists and others involved in executive coaching and consultation. Finally, it describes six commonly noted character structures in executives. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The joint WAIS-III and WMS-III factor structure: Development and cross-validation of a six-factor model of cognitive functioning.

During the standardization of the Wechsler Adult Intelligence Scale (3rd ed.; WAIS-III) and the Wechsler Memory Scale (3rd ed.; WMS-III) the participants in the normative study completed both scales. This "co-norming" methodology set the stage for full integration of the 2 tests and the development of an expanded structure of cognitive functioning. Until now, however, the WAIS-III and WMS-III had not been examined together in a factor analytic study. This article presents a series of confirmatory factor analyses to determine the joint WAIS-III and WMS-III factor structure. Using a structural equation modeling approach, a 6-factor model that included verbal, perceptual, processing speed, working memory, auditory memory, and visual memory constructs provided the best model fit to the data. Allowing select subtests to load simultaneously on 2 factors improved model fit and indicated that some subtests are multifaceted. The results were then replicated in a large cross-validation sample (N=858). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Solution dynamics and secondary structure of murine leukemia inhibitory factor: a four-helix cytokine with a rigid CD loop

Leukemia inhibitory factor (LIF) is a hematopoietic cytokine which elicits its effects on diverse cell types via both gp130 and a more specific LIF receptor. Recombinant murine LIF was studied by multidimensional homonuclear and 1H-15N heteronuclear NMR and 95% of backbone amide resonances assigned. Definition of the secondary structure by chemical shift data and NOE connectivities shows a four-alpha-helix bundle fold (helices A-D) in solution, with an additional flexible turn of helix in the AB loop. Subtle differences are seen in the conformations of helices A and D from those defined in the crystal structure [Robinson, R. C., Grey, L. M., Staunton, D., Vankelcom, H., Vernallis, A. B., Moreau, J.-F., Stuart, D. I., Heath, J. K., & Jones, E. Y. (1994) Cell77, 1101-1116]. The dynamics of the polypeptide backbone of LIF were assessed from 15N T1 and T2 relaxation times and 15N-1H heteronuclear NOEs of the amide groups. Using model-free formalism, the overall rotational correlation time of LIF in solution is calculated to be 9.7 ps. The four alpha-helices are relatively rigid, and high mobility is observed for N-terminal residues (Ser 1-Asn 21) and the AB loop. In contrast to several closely related cytokines, the long CD loop is relatively rigid. This may have implications for interactions with the specific LIF receptor, which binds in this region.     

Structural model of a cyclic dynorphin A analog bound to dodecylphosphocholine micelles by NMR and restrained molecular dynamics

The compound c[Cys5,11]dynorphin A-(1-11)-NH2, 1, is a cyclic dynorphin A analog that shows similar selectivity and potency at the kappa-opioid receptor when compared to the native form of the peptide in central nervous system assays. Previous molecular mechanics calculations have shown that the ring portion of the isoform that is trans about the Arg9-Pro10 omega bond contains either a beta-turn from residues Arg6 to Arg9 or an alpha-helical conformation. Our results from solution state NMR indicate that the compound exhibits cis-trans isomerism about the Arg9-Pro10 omega bond in both aqueous solution and when bound to dodecylphosphocholine micelles. Restrained molecular dynamics calculations show that the cis isoform of the peptide contains a type III beta-turn from residues Arg7 to Pro10. Similar calculations on the trans isoform show it to contain a beta-turn from residues Cys5 and Arg8. In this report we describe the generation of three-dimensional models from NMR data for the ring portions of both the cis and trans isoforms of 1 bound to dodecylphosphocholine micelles. Comparison with other dynorphin A structural information indicates that both the cis and trans isoforms of the peptide may be active as kappa-opioid agonists.