Anharmonicity and self-similarity of the free energy landscape of protein G

The near-native free energy landscape of protein G is investigated through 0.4 microseconds-long atomistic molecular dynamics simulations in explicit solvent. A theoretical and computational framework is used to assess the time-dependence of salient thermodynamical features. While the quasi-harmonic character of the free energy is found to degrade in a few ns, the slow modes display a very mild dependence on the trajectory duration. This property originates from a striking self-similarity of the free energy landscape embodied by the consistency of the principal directions of the local minima, where the system dwells for several ns, and of the virtual jumps connecting them.Comment: revtex, 6 pages, 5 figure

Glass transition in biomolecules and the liquid-liquid critical point of water

Using molecular dynamics simulations, we investigate the relation between the dynamic transitions of biomolecules (lysozyme and DNA) and the dynamic and thermodynamic properties of hydration water. We find that the dynamic transition of the macromolecules, sometimes called a ``protein glass transition'', occurs at the temperature of dynamic crossover in the diffusivity of hydration water, and also coincides with the maxima of the isobaric specific heat $C_P$ and the temperature derivative of the orientational order parameter. We relate these findings to the hypothesis of a liquid-liquid critical point in water. Our simulations are consistent with the possibility that the protein glass transition results from crossing the Widom line, which is defined as the locus of correlation length maxima emanating from the hypothesized second critical point of water.Comment: 10 Pages, 12 figure

Molecular dynamics simulation of nanocolloidal amorphous silica particles: Part II

Explicit molecular dynamics simulations were applied to a pair of amorphous silica nanoparticles of diameter 3.2 nm immersed in a background electrolyte. Mean forces acting between the pair of silica nanoparticles were extracted at four different background electrolyte concentrations. Dependence of the inter-particle potential of mean force on the separation and the silicon to sodium ratio, as well as on the background electrolyte concentration, are demonstrated. The pH was indirectly accounted for via the ratio of silicon to sodium used in the simulations. The nature of the interaction of the counter-ions with charged silica surface sites (deprotonated silanols) was also investigated. The effect of the sodium double layer on the water ordering was investigated for three Si:Na+ ratios. The number of water molecules trapped inside the nanoparticles was investigated as the Si:Na+ ratio was varied. Differences in this number between the two nanoparticles in the simulations are attributed to differences in the calculated electric dipole moment. The implications of the form of the potentials for aggregation are also discussed.Comment: v1. 33 pages, 7 figures (screen-quality PDF), submitted to J. Chem. Phys v2. 15 pages, 4 tables, 6 figures. Content, author list and title changed; single space

Feasibility of single-order parameter description of equilibrium viscous liquid dynamics

Molecular dynamics results for the dynamic Prigogine-Defay ratio are presented for two glass-forming liquids, thus evaluating the experimentally relevant quantity for testing whether metastable-equilibrium liquid dynamics to a good approximation are described by a single parameter. For the Kob-Andersen binary Lennard-Jones mixture as well as for an asymmetric dumbbell model liquid a single-parameter description works quite well. This is confirmed by time-domain results where it is found that energy and pressure fluctuations are strongly correlated on the alpha-time scale in the NVT ensemble; in the NpT ensemble energy and volume fluctuations similarly correlate strongly.Comment: Phys. Rev. E, in pres

IPEP: The integrated performance evaluation program for the Department of Energy`s Office of Environmental Management

The quality of the analytical data being provided to DOE`s Office of Environmental Management (EM) for environmental restoration activities and the extent to which these data meet the data quality objectives are critical in the decision-making process. One of several quality metrics that can be used in evaluating a laboratory is its performance in performance evaluation (PE) programs. In support of DOE`s environmental restoration and waste management efforts, EM has been charged with developing and implementing a program to assess the performance of participating laboratories. Argonne National Laboratory (ANL) and DOE`s Environmental Measurements Laboratory (EML) and Radiological and Environmental Sciences Laboratory (RESL) have been collaborating on the development and implementation of a comprehensive Integrated Performance Evaluation Program (IPEP) for DOE-wide implementation. The IPEP will use results from existing inorganic, organic, and radiological PE programs when these are available and appropriate for the analytes and matrices being determined for DOE`s EM activities. Existing programs include the U.S. Environmental Protection Agency`s (EPA`s) Contract Laboratory Program (CLP), the Water Supply (WS) and Water Pollution (WP) PE studies for inorganic and organic analytes, and DOE`s Quality Assessment Program (QAP) for radiological analytes. In addition, DOE has begun the development of the Mixed Analyte Performance Evaluation Program (MAPEP) to address the needs of the DOE Complex. These PE programs provide a spectrum of matrices and analytes covering the various inorganic, organic, and low-level radiologic categories found in routine environmental and waste samples. These PE programs already provide some assessment of laboratory performance; IPEP will expand these assessments by evaluating historical performance, as well as results from multiple PE programs, thereby providing an enhanced usage of the PE program information

Influence of conformational fluctuations on enzymatic activity: modelling the functional motion of beta-secretase

Considerable insight into the functional activity of proteins and enzymes can be obtained by studying the low-energy conformational distortions that the biopolymer can sustain. We carry out the characterization of these large scale structural changes for a protein of considerable pharmaceutical interest, the human $\beta$-secretase. Starting from the crystallographic structure of the protein, we use the recently introduced beta-Gaussian model to identify, with negligible computational expenditure, the most significant distortion occurring in thermal equilibrium and the associated time scales. The application of this strategy allows to gain considerable insight into the putative functional movements and, furthermore, helps to identify a handful of key regions in the protein which have an important mechanical influence on the enzymatic activity despite being spatially distant from the active site. The results obtained within the Gaussian model are validated through an extensive comparison against an all-atom Molecular Dynamics simulation.Comment: To be published in a special issue of J. Phys.: Cond. Mat. (Bedlewo Workshop

Driving calmodulin protein towards conformational shift by changing ionization states of select residues

Proteins are complex systems made up of many conformational sub-states which are mainly determined by the folded structure. External factors such as solvent type, temperature, pH and ionic strength play a very important role in the conformations sampled by proteins. Here we study the conformational multiplicity of calmodulin (CaM) which is a protein that plays an important role in calcium signaling pathways in the eukaryotic cells. CaM can bind to a variety of other proteins or small organic compounds, and mediates different physiological processes by activating various enzymes. Binding of calcium ions and proteins or small organic molecules to CaM induces large conformational changes that are distinct to each interacting partner. In particular, we discuss the effect of pH variation on the conformations of CaM. By using the pKa values of the charged residues as a basis to assign protonation states, the conformational changes induced in CaM by reducing the pH are studied by molecular dynamics simulations. Our current view suggests that at high pH, barrier crossing to the compact form is prevented by repulsive electrostatic interactions between the two lobes. At reduced pH, not only is barrier crossing facilitated by protonation of residues, but also conformations which are on average more compact are attained. The latter are in accordance with the fluorescence resonance energy transfer experiment results of other workers. The key events leading to the conformational change from the open to the compact conformation are (i) formation of a salt bridge between the N-lobe and the linker, stabilizing their relative motions, (ii) bending of the C-lobe towards the N-lobe, leading to a lowering of the interaction energy between the two-lobes, (iii) formation of a hydrophobic patch between the two lobes, further stabilizing the bent conformation by reducing the entropic cost of the compact form, (iv) sharing of a Ca+2 ion between the two lobes

Outer-Sphere Contributions to the Electronic Structure of Type Zero Copper Proteins

Bioinorganic canon states that active-site thiolate coordination promotes rapid electron transfer (ET) to and from type 1 copper proteins. In recent work, we have found that copper ET sites in proteins also can be constructed without thiolate ligation (called “type zero” sites). Here we report multifrequency electron paramagnetic resonance (EPR), magnetic circular dichroism (MCD), and nuclear magnetic resonance (NMR) spectroscopic data together with density functional theory (DFT) and spectroscopy-oriented configuration interaction (SORCI) calculations for type zero Pseudomonas aeruginosa azurin variants. Wild-type (type 1) and type zero copper centers experience virtually identical ligand fields. Moreover, O-donor covalency is enhanced in type zero centers relative that in the C112D (type 2) protein. At the same time, N-donor covalency is reduced in a similar fashion to type 1 centers. QM/MM and SORCI calculations show that the electronic structures of type zero and type 2 are intimately linked to the orientation and coordination mode of the carboxylate ligand, which in turn is influenced by outer-sphere hydrogen bonding