Time scales for transitions between free-energy minima of a dense hard-sphere system

Time scales associated with activated transitions between glassy metastable states of a free-energy functional appropriate for a dense hard-sphere system are calculated by using a new Monte Carlo method for the local density variables. In particular, we calculate the time the system, initially placed in a shallow glassy minimum of the free-energy, spends in the neighborhood of this minimum before making a transition to the basin of attraction of another free-energy minimum. This time scale is found to increase as the average density is increased. We find a crossover density near which this time scale increases very sharply and becomes longer than the longest times accessible in our simulation. This time scale does not show any evidence of increasing with sample size

DNA Free Energy-Based Promoter Prediction and Comparative Analysis of Arabidopsis and Rice Genomes

The cis-regulatory regions on DNA serve as binding sites for proteins such as transcription factors and RNA polymerase. The combinatorial interaction of these proteins plays a crucial role in transcription initiation, which is an important point of control in the regulation of gene expression. We present here an analysis of the performance of an in silico method for predicting cis-regulatory regions in the plant genomes of Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) on the basis of free energy of DNA melting. For protein-coding genes, we achieve recall and precision of 96% and 42% for Arabidopsis and 97% and 31% for rice, respectively. For noncoding RNA genes, the program gives recall and precision of 94% and 75% for Arabidopsis and 95% and 90% for rice, respectively. Moreover, 96% of the false-positive predictions were located in noncoding regions of primary transcripts, out of which 20% were found in the first intron alone, indicating possible regulatory roles. The predictions for orthologous genes from the two genomes showed a good correlation with respect to prediction scores and promoter organization. Comparison of our results with an existing program for promoter prediction in plant genomes indicates that our method shows improved prediction capability.

A molecular dynamics study based post facto free energy analysis of the binding of bovine angiogenin with UMP and CMP ligands

Angiogenin is a protein belonging to the superfamily of RNase A. The RNase activity of this protein is essential for its angiogenic activity. Although members of the RNase A family carry out RNase activity, they differ markedly in their strength and specificity. In this paper, we address the problem of higher specificity of angiogenin towards cytosine against uracil in the first base binding position. We have carried out extensive nano-second level molecular dynamics(MD) computer simulations on the native bovine angiogenin and on the CMP and UMP complexes of this protein in aqueous medium with explicit molecular solvent. The structures thus generated were subjected to a rigorous free energy component analysis to arrive at a plausible molecular thermodynamic explanation for the substrate specificity of angiogenin.

Estimation of surface free energy of pyrites by contact angle measurements

The surface properties of coal-pyrite play a major role in determining its separation from coal in processes such as flotation. The solution pH is an important parameter in determining the surface properties of both coal and coal-pyrite such as surface free energy and zeta-potential. In the present investigation, the effect of pH on the surface free energy of pyrites from different sources was studied. The surface free energy of solids is made up of two components, i.e. the dispersive surface free energy and the acid-base interaction energy. Various methods have been used by previous researchers to evaluate these two components for different solids. In the present study, a new approach was developed and used to study the surface free energy of pyrite surfaces. Results indicate that the dispersion surface free energy of various pyrites is independent of pH while the acid-base interaction energy is strongly dependent on the pH. The acid-base interaction energy is different for each pyrite sample and also the change with pH varies with the type of pyrite. Coal-pyrite was found to be more hydrophobic than ore-pyrite which may be attributed to the presence of carbon in coal-pyrites. The acid-base interaction energy varied little with pH for coal pyrites than ore-pyrite. Comparison of acid-base interaction energy with zeta-potential measurements shows a good correlation between the minimum in acid-base interaction energy and the pHpzc.

Understanding glassy dynamics from the free-energy landscape

Many interesting features of the dynamics of simple liquids near the glass transition may be understood in terms of properties of the free-energy landscape obtained from numerical studies of a model free-energy functional. Main results obtained from this approach are summarized and a list of references to relevant publications is provided. (C) 2002 Elsevier Science B.V. All rights reserved.

Docking and free energy simulations to predict conformational domains involved in hCG-LH receptor interactions using recombinant antibodies

Single chain fragment variables (ScFvs) have been extensively employed in studying the protein-protein interactions. ScFvs derived from phage display libraries have an additional advantage of being generated against a native antigen, circumventing loss of information on conformational epitopes. In the present study, an attempt has been made to elucidate human chorionic gonadotropin (hCG)-luteinizing hormone (LH) receptor interactions by using a neutral and two inhibitory ScFvs against hCG. The objective was to dock a computationally derived model of these ScFvs onto the crystal structure of hCG and understand the differential roles of the mapped epitopes in hCG-LH receptor interactions. An anti-hCG ScFv, whose epitope was mapped previously using biochemical tools, served as the positive control for assessing the quality of docking analysis. To evaluate the role of specific side chains at the hCG-ScFv interface, binding free energy as well as residue interaction energies of complexes in solution were calculated using molecular mechanics Poisson-Boltzmann/surface area method after performing the molecular dynamic simulations on the selected hCG-ScFv models and validated using biochemical and SPR analysis. The robustness of these calculations was demonstrated by comparing the theoretically determined binding energies with the experimentally obtained kinetic parameters for hCG-ScFv complexes. Superimposition of hCG-ScFv model onto a model of hCG complexed with the 51-266 residues of LH receptor revealed importance of the residues previously thought to be unimportant for hormone binding and response. This analysis provides an alternate tool for understanding the structure-function analysis of ligand-receptor interactions. Proteins 2011;79:3108-3122. (C) 2011 Wiley-Liss, Inc.

Gibbs free energies of formation of ZnAl2O4 and ZnCr2O4

The standard free energies of formation of zinc aluminate and chromite were determined by measuring the oxygen potential over a solid CuZn alloy, containing 10 at.−% Zn, in equilibrium with ZnO, ZnAl2O4+Al2O3(χ) and ZnCr2O4+Cr2O3, in the temperature range 700–900°C. The oxygen potential was monitored by means of a solid oxide galvanic cell in which a Y2O3 ThO2 pellet was sandwiched between a CaOZrO2 crucible and tube. The temperature dependence of the free energies of formation of the interoxidic compounds can be represented by the equations, The heat of formation of the spinels calculated from the measurements by the “Second Law method” is found to be in good agreement with calorimetrically determined values. Using an empirical correlation for the entropy of formation of cubic spinel phases from oxides with rock-salt and corundum structures and the measured high temperature cation distribution in ZnAl2O4, the entropy of transformation of ZnO from wurtzite to rock-salt structure is evaluated.

Phase relations and Gibbs energies of spinel phases and solid solutions in the system Mg-Rh-O

Pure stoichiometric MgRh(2)O(4) could not be prepared by solid state reaction from an equimolar mixture of MgO and Rh(2)O(3) in air. The spinel phase formed always contained excess of Mg and traces of Rh or Rh(2)O(3). The spinel phase can be considered as a solid solution of Mg(2)RhO(4) in MgRh(2)O(4). The compositions of the spinel solid solution in equilibrium with different phases in the ternary system Mg-Rh-O were determined by electron probe microanalysis. The oxygen potential established by the equilibrium between Rh + MgO + Mg(1+x)Rh(2-x)O(4) was measured as a function of temperature using a solid-state cell incorporating yttria-stabilized zirconia as an electrolyte and pure oxygen at 0.1 MPa as the reference electrode. To avoid polarization of the working electrode during the measurements, an improved design of the cell with a buffer electrode was used. The standard Gibbs energies of formation of MgRh(2)O(4) and Mg(2)RhO(4) were deduced from the measured electromotive force (e.m.f.) by invoking a model for the spinel solid solution. The parameters of the model were optimized using the measured composition of the spinel solid solution in different phase fields and imposed oxygen partial pressures. The results can be summarized by the equations: MgO + beta -Rh(2)O(3) -> MgRh(2)O(4); Delta G degrees (+ 1010)/J mol(-1) = -32239 + 7.534T; 2MgO + RhO(2) -> Mg(2)RhO(4); Delta G degrees(+/- 1270)/J mol(-1) = 36427 -4.163T; Delta G(M)/J mol(-1) = 2RT(xInx + (1-x)In(1-x)) + 4650x(1-x), where Delta G degrees is the standard Gibbs free energy change for the reaction and G(M) is the free energy of mixing of the spinel solid solution Mg(1+x)Rh(2-x)O(4). (C) 2011 Elsevier B. V. All rights reserved.

Free Energy Barriers for Escape of Water Molecules from Protein Hydration Layer

Free energy barriers separating interfacial water molecules from the hydration layer at the surface of a protein to the bulk are obtained by using the umbrella sampling method of free energy calculation. We consider hydration layer of chicken villin head piece (HP-36) which has been studied extensively by molecular dynamics simulations. The free energy calculations reveal a strong sensitivity to the secondary structure. In particular, we find a region near the junction of first and second helix that contains a cluster of water molecules which are slow in motion, characterized by long residence times (of the order of 100 ps or more) and separated by a large free energy barrier from the bulk water. However, these ``slow'' water molecules constitute only about 5-10% of the total number of hydration layer water molecules. Nevertheless, they play an important role in stabilizing the protein conformation. Water molecules near the third helix (which is the important helix for biological function) are enthalpically least stable and exhibit the fastest dynamics. Interestingly, barrier height distributions of interfacial water are quite broad for water surrounding all the three helices (and the three coils), with the smallest barriers found for those near the helix-3. For the quasi-bound water molecules near the first and second helices, we use well-known Kramers' theory to estimate the residence time from the free energy surface, by estimating the friction along the reaction coordinate from the diffusion coefficient by using Einstein relation. The agreement found is satisfactory. We discuss the possible biological function of these slow, quasi-bound (but transient) water molecules on the surface.

Characterization of structural and free energy properties of promoters associated with Primary and Operon TSS in Helicobacter pylori genome and their orthologs

Promoter regions in the genomes of all domains of life show similar trends in several structural properties such as stability, bendability, curvature, etc. In current study we analysed the stability and bendability of various classes of promoter regions (based on the recent identification of different classes of transcription start sites) of Helicobacter pylori 26695 strain. It is found that primary TSS and operon-associated TSS promoters show significantly strong features in their promoter regions. DNA free-energy-based promoter prediction tool PromPredict was used to annotate promoters of different classes, and very high recall values (similar to 80%) are obtained for primary TSS. Orthologous genes from other strains of H. pylori show conservation of structural properties in promoter regions as well as coding regions. PromPredict annotates promoters of orthologous genes with very high recall and precision.

Free energy barriers for homogeneous crystal nucleation in a eutectic system of binary hard spheres

In this study, the free energy barriers for homogeneous crystal nucleation in a system that exhibits a eutectic point are computed using Monte Carlo simulations. The system studied is a binary hard sphere mixture with a diameter ratio of 0.85 between the smaller and larger hard spheres. The simulations of crystal nucleation are performed for the entire range of fluid compositions. The free energy barrier is found to be the highest near the eutectic point and is nearly five times that for the pure fluid, which slows down the nucleation rate by a factor of 10(-31). These free energy barriers are some of highest ever computed using simulations. For most of the conditions studied, the composition of the critical nucleus corresponds to either one of the two thermodynamically stable solid phases. However, near the eutectic point, the nucleation barrier is lowest for the formation of the metastable random hexagonal closed packed (rhcp) solid phase with composition lying in the two-phase region of the phase diagram. The fluid to solid phase transition is hypothesized to proceed via formation of a metastable rhcp phase followed by a phase separation into respective stable fcc solid phases.

Communication: Benzene dimer-The free energy landscape

Establishing the relative orientation of the two benzene molecules in the dimer has remained an enigmatic challenge. Consensus has narrowed the choice of structures to either a T-shape, that may be tilted, or a parallel displaced arrangement, but the relatively small energy differences makes identifying the global minimum difficult. Here we report an ab initio Car-Parrinello Molecular Dynamics based metadynamics computation of the free-energy landscape of the benzene dimer. Our calculations show that although competing structures may be isoenergetic, free energy always favors a tilted T-shape geometry at all temperatures where the bound benzene dimer exist. (C) 2013 AIP Publishing LLC.

Propensity to Form Amyloid Fibrils Is Encoded as Excitations in the Free Energy Landscape of Monomeric Proteins

Protein aggregation, linked to many of diseases, is initiated when monomers access rogue conformations that are poised to form amyloid fibrils. We show, using simulations of src SH3 domain, that mechanical force enhances the population of the aggregation-prone (N*) states, which are rarely populated under force free native conditions but are encoded in the spectrum of native fluctuations. The folding phase diagrams of SH3 as a function of denaturant concentration (C]), mechanical force (f), and temperature exhibit an apparent two-state behavior, without revealing the presence of the elusive N* states. Interestingly, the phase boundaries separating the folded and unfolded states at all C] and f fall on a master curve, which can be quantitatively described using an analogy to superconductors in a magnetic field. The free energy profiles as a function of the molecular extension (R), which are accessible in pulling experiments, (R), reveal the presence of a native-like N* with a disordered solvent-exposed amino-terminal beta-strand. The structure of the N* state is identical with that found in Fyn SH3 by NMR dispersion experiments. We show that the timescale for fibril formation can be estimated from the population of the N* state, determined by the free energy gap separating the native structure and the N* state, a finding that can be used to assess fibril forming tendencies of proteins. The structures of the N* state are used to show that oligomer formation and likely route to fibrils occur by a domain-swap mechanism in SH3 domain. (C) 2014 Elsevier Ltd. All rights reserved.