Protein-ligand binding free energy estimation using molecular mechanics and continuum electrostatics. Application to HIV-1 protease inhibitors.

A method is proposed for the estimation of absolute binding free energy of interaction between proteins and ligands. Conformational sampling of the protein-ligand complex is performed by molecular dynamics (MD) in vacuo and the solvent effect is calculated a posteriori by solving the Poisson or the Poisson-Boltzmann equation for selected frames of the trajectory. The binding free energy is written as a linear combination of the buried surface upon complexation, SASbur, the electrostatic interaction energy between the ligand and the protein, Eelec, and the difference of the solvation free energies of the complex and the isolated ligand and protein, deltaGsolv. The method uses the buried surface upon complexation to account for the non-polar contribution to the binding free energy because it is less sensitive to the details of the structure than the van der Waals interaction energy. The parameters of the method are developed for a training set of 16 HIV-1 protease-inhibitor complexes of known 3D structure. A correlation coefficient of 0.91 was obtained with an unsigned mean error of 0.8 kcal/mol. When applied to a set of 25 HIV-1 protease-inhibitor complexes of unknown 3D structures, the method provides a satisfactory correlation between the calculated binding free energy and the experimental pIC5o without reparametrization.

Modelling the super-equilibria in thermal biomass conversion : applications and limitations of the constrained free energy method

Bioenergi ses som en viktig del av det nu- och framtida sortimentet av inhemsk energi. Svartlut, bark och skogsavfall täcker mer än en femtedel av den inhemska energianvändningen. Produktionsanläggningar kan fungera ofullständigt och en mängd gas-, partikelutsläpp och tjära produceras samtidigt och kan leda till beläggningsbildning och korrosion. Orsaken till dessa problem är ofta obalans i processen: vissa föreningar anrikas i processen och superjämviktstillstånd är bildas. I denna doktorsavhandling presenteras en ny beräkningsmetod, med vilken man kan beskriva superjämviktstillståndet, de viktigaste kemiska reaktionerna, processens värmeproduktion och tillståndsstorheter samtidigt. Beräkningsmetoden grundar sig på en unik frienergimetod med bivillkor som har utvecklats vid VTT. Den här så kallade CFE-metoden har tidigare utnyttjats i pappers-, metall- och kemiindustrin. Applikationer för bioenergi, vilka är demonstrerade i doktorsavhandlingen, är ett nytt användingsområde för metoden. Studien visade att beräkningsmetoden är väl lämpad för högtemperaturenergiprocesser. Superjämviktstillstånden kan uppstå i dessa processer och det kemiska systemet kan definieras med några bivillkor. Typiska tillämpningar är förbränning av biomassa och svartlut, förgasning av biomassa och uppkomsten av kväveoxider. Också olika sätt att definiera superjämviktstillstånd presenterades i doktorsavhandlingen: empiriska konstanter, empiriska hastighetsuttryck eller reaktionsmekanismer kan användas. Resultaten av doktorsavhandlingen kan utnyttjas i framtiden i processplaneringen och i undersökning av nya tekniska lösningar för förgasning, förbränningsteknik och biobränslen. Den presenterade metoden är ett bra alternativ till de traditionella mekanistiska och fenomenmodeller och kombinerar de bästa delarna av både. --------------------------------------------------------------- Bioenergia on tärkeä osa nykyistä ja tulevaa kotimaista energiapalettia. Mustalipeä, kuori ja metsätähteet kattavat yli viidenneksen kotimaisesta energian kulutuksesta. Tuotantolaitokset eivät kuitenkaan aina toimi täydellisesti ja niiden prosesseissa syntyy erilaisia kaasu- ja hiukkaspäästöjä, tervoja sekä prosessilaitteita kuluttavia saostumia ja ruostumista. Usein syy näihin ongelmiin on prosessissa esiintyvä epätasapainotila: tietyt yhdisteet rikastuvat prosessissa ja muodostavat supertasapainotiloja. Väitöstyössä kehitettiin uusi laskentamenetelmä, jolla voidaan kuvata nämä supertasapainotilat, tärkeimmät niihin liittyvät kemialliset reaktiot, prosessin lämmöntuotanto ja tilansuureet yhtä aikaa. Laskentamenetelmä perustuu VTT:llä kehitettyyn ainutlaatuiseen rajoitettuun vapaaenergiamenetelmään. Tätä niin kutsuttua CFE-menetelmää on aiemmin sovelluttu onnistuneesti muun muassa paperi-, metalli- ja kemianteollisuudessa. Väitöstyössä esitetyt bioenergiasovellukset ovat uusi sovellusalue menetelmälle. Työ osoitti laskentatavan soveltuvan hyvin korkealämpöisiin energiatekniikan prosesseihin, joissa kemiallista systeemiä rajoittavia tekijöitä oli rajallinen määrä ja siten super-tasapainotila saattoi muodostua prosessin aikana. Tyypillisiä sovelluskohteita ovat biomassan ja mustalipeän poltto, biomassan kaasutus ja typpioksidipäästöt. Työn aikana arvioitiin myös erilaisia tapoja määritellä super-tasapainojen muodostumista rajoittavat tekijät. Rajoitukset voitiin tehdä teollisiin mittauksiin pohjautuen, kokeellisia malleja hyödyntäen tai mekanistiseen reaktiokinetiikkaan perustuen. Tulevaisuudessa väitöstyön tuloksia voidaan hyödyntää prosessisuunnittelussa ja tutkittaessa uusia teknisiä ratkaisuja kaasutus- ja polttotekniikoissa sekä biopolttoaineiden tutkimuksessa. Kehitetty menetelmä tarjoaa hyvän vaihtoehdon perinteisille mekanistisille ja ilmiömalleille yhdistäen näiden parhaita puolia.

Anharmonic Helmholtz free energy to O(lambdaâ ´) in the non- leading term approximation /|nby Leslie Wilk. -- 260 St. Catharines, Ont. : [s. n.],

Expressions for the anharmonic Helmholtz free energy contributions up to o( f ) ,valid for all temperatures, have been obtained using perturbation theory for a c r ystal in which every atom is on a site of inversion symmetry. Numerical calculations have been carried out in the high temperature limit and in the non-leading term approximation for a monatomic facecentred cubic crystal with nearest neighbour c entralforce interactions. The numbers obtained were seen to vary by a s much as 47% from thos e obtai.ned in the leading term approximati.on,indicating that the latter approximati on is not in general very good. The convergence to oct) of the perturbation series in the high temperature limit appears satisfactory.

On the Ewald method and the quartic Helmholtz free energy of an anharmonic metallic crystal

Thesis (M. Sc.) - Brock University, 1978.

An anharmonic contribution to the Helmholtz free energy O(lambda 6)

The anharmonic contributions of order A6 to the Helmholtz free energy for a crystal in which every atom is on a site of inversion symmetry, have been evaluated The cor~esponding diagrams in the various orders of the perturbation theory have been presented The validity of the expressions given is for high temperatures. Numerical calculations for the diagrams which contribute to the free energy have been worked out for a nearest-n~ighbour central-force model of a facecentered cubic lattice in the high-temperature limit and in the leading term and the Ludwig approximations. The accuracy of the Ludwig approximation in evaluating the Brillouin-zone sums has been investigated. Expansion for all diagrams in the high-temperature limit has been carried out The contribution to the specific heat involves a linear as well as cubic term~ We have applied Lennard-Jones, Morse and Exponential 6 types of potentials. A comparison between the contribution to the free energy of order A6 to that of order A4 has been made.

Glycogen phosphorylase inhibitors: a free energy perturbation analysis of glucopyranose spirohydantoin analogues

GP catalyzes the phosphorylation of glycogen to Glc-1-P. Because of its fundamental role in the metabolism of glycogen, GP has been the target for a systematic structure-assisted design of inhibitory compounds, which could be of value in the therapeutic treatment of type 2 diabetes mellitus. The most potent catalytic-site inhibitor of GP identified to date is spirohydantoin of glucopyranose (hydan). In this work, we employ MD free energy simulations to calculate the relative binding affinities for GP of hydan and two spirohydantoin analogues, methyl-hydan and n-hydan, in which a hydrogen atom is replaced by a methyl- or amino group, respectively. The results are compared with the experimental relative affinities of these ligands, estimated by kinetic measurements of the ligand inhibition constants. The calculated binding affinity for methyl-hydan (relative to hydan) is 3.75 +/- 1.4 kcal/mol, in excellent agreement with the experimental value (3.6 +/- 0.2 kcal/mol). For n-hydan, the calculated value is 1.0 +/- 1.1 kcal/mol, somewhat smaller than the experimental result (2.3 +/- 0.1 kcal/mol). A free energy decomposition analysis shows that hydan makes optimum interactions with protein residues and specific water molecules in the catalytic site. In the other two ligands, structural perturbations of the active site by the additional methyl- or amino group reduce the corresponding binding affinities. The computed binding free energies are sensitive to the preference of a specific water molecule for two well-defined positions in the catalytic site. The behavior of this water is analyzed in detail, and the free energy profile for the translocation of the water between the two positions is evaluated. The results provide insights into the role of water molecules in modulating ligand binding affinities. A comparison of the interactions between a set of ligands and their surrounding groups in X-ray structures is often used in the interpretation of binding free energy differences and in guiding the design of new ligands. For the systems in this work, such an approach fails to estimate the order of relative binding strengths, in contrast to the rigorous free energy treatment.

Methodologies for the generation of design summer years for building energy simulation using UKCP09 probabilitic climate projections

Design summer years representing near-extreme hot summers have been used in the United Kingdom for the evaluation of thermal comfort and overheating risk. The years have been selected from measured weather data basically representative of an assumed stationary climate. Recent developments have made available ‘morphed’ equivalents of these years by shifting and stretching the measured variables using change factors produced by the UKCIP02 climate projections. The release of the latest, probabilistic, climate projections of UKCP09 together with the availability of a weather generator that can produce plausible daily or hourly sequences of weather variables has opened up the opportunity for generating new design summer years which can be used in risk-based decision-making. There are many possible methods for the production of design summer years from UKCP09 output: in this article, the original concept of the design summer year is largely retained, but a number of alternative methodologies for generating the years are explored. An alternative, more robust measure of warmth (weighted cooling degree hours) is also employed. It is demonstrated that the UKCP09 weather generator is capable of producing years for the baseline period, which are comparable with those in current use. Four methodologies for the generation of future years are described, and their output related to the future (deterministic) years that are currently available. It is concluded that, in general, years produced from the UKCP09 projections are warmer than those generated previously. Practical applications: The methodologies described in this article will facilitate designers who have access to the output of the UKCP09 weather generator (WG) to generate Design Summer Year hourly files tailored to their needs. The files produced will differ according to the methodology selected, in addition to location, emissions scenario and timeslice.

Influence of probabilistic climate projections on building energy simulation

The Chartered Institute of Building Service Engineers (CIBSE) produced a technical memorandum (TM36) presenting research on future climate impacting building energy use and thermal comfort. One climate projection for each of four CO2 emissions scenario were used in TM36, so providing a deterministic outlook. As part of the UK Climate Impacts Programme (UKCIP) probabilistic climate projections are being studied in relation to building energy simulation techniques. Including uncertainty in climate projections is considered an important advance to climate impacts modelling and is included in the latest UKCIP data (UKCP09). Incorporating the stochastic nature of these new climate projections in building energy modelling requires a significant increase in data handling and careful statistical interpretation of the results to provide meaningful conclusions. This paper compares the results from building energy simulations when applying deterministic and probabilistic climate data. This is based on two case study buildings: (i) a mixed-mode office building with exposed thermal mass and (ii) a mechanically ventilated, light-weight office building. Building (i) represents an energy efficient building design that provides passive and active measures to maintain thermal comfort. Building (ii) relies entirely on mechanical means for heating and cooling, with its light-weight construction raising concern over increased cooling loads in a warmer climate. Devising an effective probabilistic approach highlighted greater uncertainty in predicting building performance, depending on the type of building modelled and the performance factors under consideration. Results indicate that the range of calculated quantities depends not only on the building type but is strongly dependent on the performance parameters that are of interest. Uncertainty is likely to be particularly marked with regard to thermal comfort in naturally ventilated buildings.

The Landau free energy of hard ellipses obtained from microscopic simulations

Systems of two-dimensional hard ellipses of varying aspect ratios and packing fractions are studied by Monte Carlo simulations in the generalised canonical ensemble. From this microscopic model, we extract a coarse-grained macroscopic Landau-de Gennes free energy as a function of packing fraction and orientational order parameter. We separate the free energy into the ideal orientational entropy of non-interacting two-dimensional spins and an excess free energy associated with excluded volume interactions. We further explore the isotropic-nematic phase transition using our empirical expression for the free energy and find that the nature of the phase transition is continuous for the aspect ratios we studied.

Solvatochromism in Binary Mixtures: First Report on a Solvation Free Energy Relationship between Solvent Exchange Equilibrium Constants and the Properties of the Medium

We have employed UV-vis spectroscopy in order to investigate details of the solvation of six solvatochromic indicators, hereafter designated as ""probes"", namely, 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1-yl) phenolate (RB); 4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePM; 1-methylquinolinium-8-olate, QB; 2-bromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr, 2,6-dichloro-4-(2,4,6-triphenylpyridinium-1-yl) phenolate (WB); and 2,6-dibromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr,, respectively. These can be divided into three pairs, each includes two probes of similar pK(a) in water and different lipophilicity. Solvation has been studied in binary mixtures, BMs, of water, W, with 12 protic organic solvents, S, including mono- and bifunctional alcohols (2-alkoxyethanoles, unsaturated and chlorinated alcohols). Each medium was treated as a mixture of S, W, and a complex solvent, S-W, formed by hydrogen bonding. Values of lambda(max) (of the probe intramolecular charge transfer) were converted into empirical polarity scales, E(T)(probe) in kcal/mol, whose values were correlated with the effective mole fraction of water in the medium, chi w(effective). This correlation furnished three equilibrium constants for the exchange of solvents in the probe solvation shell; phi(W/S) (W substitutes S): phi(S-W/W) (S-W substitutes W), and phi(S-W/S) (S-W substitutes S), respectively. The values of these constants depend on the physicochemical properties of the probe and the medium. We tested, for the first time, the applicability of a new solvation free energy relationship: phi = constant + a alpha(BM) + b beta(BM) + s(pi*(BM) + d delta) + p log P(BM), where a, b, s, and p are regression coefficients alpha(BM), beta(BM), and pi*(BM) are solvatochromic parameters of the BM, delta is a correction term for pi*, and log P is an empirical scale of lipophilicity. Correlations were carried out with two-, three-, and four-medium descriptors. In all cases, three descriptors gave satisfactory correlations; use of four parameters gave only a marginal increase of the goodness of fit. For phi(W/S), the most important descriptor was found to be the lipophilicity of the medium; for phi(S-W/W) and phi(S-W/S), solvent basicity is either statistically relevant or is the most important descriptor. These responses are different from those of E(T)(probe) of many solvatochromic indicators in pure solvents, where the importance of solvent basicity is usually marginal, and can be neglected.

Energy savings potential in existing houses : Energy simulation results for Dalarna's single-family housing stock

Vägar till en halverad energianvändning i Dalarnas byggnadsbestånd

Hydropower Energy Simulation Using Mike 11 Model; A Case Study In South Germany's Small Run-Of-River Hydropower Plants

Renewable energy production is a basic supplement to stabilize rapidly increasing global energy demand and skyrocketing energy price as well as to balance the fluctuation of supply from non-renewable energy sources at electrical grid hubs. The European energy traders, government and private company energy providers and other stakeholders have been, since recently, a major beneficiary, customer and clients of Hydropower simulation solutions. The relationship between rainfall-runoff model outputs and energy productions of hydropower plants has not been clearly studied. In this research, association of rainfall, catchment characteristics, river network and runoff with energy production of a particular hydropower station is examined. The essence of this study is to justify the correspondence between runoff extracted from calibrated catchment and energy production of hydropower plant located at a catchment outlet; to employ a unique technique to convert runoff to energy based on statistical and graphical trend analysis of the two, and to provide environment for energy forecast. For rainfall-runoff model setup and calibration, MIKE 11 NAM model is applied, meanwhile MIKE 11 SO model is used to track, adopt and set a control strategy at hydropower location for runoff-energy correlation. The model is tested at two selected micro run-of-river hydropower plants located in South Germany. Two consecutive calibration is compromised to test the model; one for rainfall-runoff model and other for energy simulation. Calibration results and supporting verification plots of two case studies indicated that simulated discharge and energy production is comparable with the measured discharge and energy production respectively.

Strand Analysis, a free online program for the computational identification of the best RNA interference (RNAi) targets based on Gibbs free energy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)