Blinded predictions of standard binding free energies: lessons learned from the SAMPL6 challenge

<p>In the context of the SAMPL6 challenges, series of blinded predictions of standard binding free energies were made with the SOMD software for a dataset of 27 host-guest systems featuring two octa-acids hosts (<i>OA </i>and <i>TEMOA) </i>and a cucuribituril ring (<i>CB</i>8)<i> </i>host. Three different models were used, <i>ModelA </i>computes the free energy of binding based on a double annihilation technique; <i>ModelB</i> additionally takes into account long-range dispersion and standard state corrections; <i>ModelC</i> additionally introduces an empirical correction term derived from a regression analysis of SAMPL5 predictions previously made with SOMD. The performance of each model was evaluated with two different setups; <i>buffer </i>explicitly matches the ionic strength from the binding assays, whereas <i>no-buffer</i> merely neutralizes the host-guest net charge with counter-ions. <i>ModelC/no-buffer</i> shows the lowest mean-unsigned error for the overall dataset (MUE 1.29 < 1.39 < 1.50 kcal mol^-1, 95% CI), while explicit modelling of the buffer improves significantly results for the CB8 host only. Correlation with experimental data ranges from excellent for the host TEMOA (R² 0.91 < 0.94 < 0.96), to poor for <i>CB8 </i>(R² 0.04 < 0.12 < 0.23). Further investigations indicate a pronounced dependence of the binding free energies on the modelled ionic strength, and variable reproducibility of the binding free energies between different simulation packages. </p

New molecular simulation methods for quantitative modelling of protein-ligand interactions

The main theme of this work is the design and development of new molecular simulation protocols, to achieve more accurate and reliable estimates of free energy changes for processes relevant to the structure-based drug design. The works starts with an insight into the reproducibility problem for alchemical free energy calculations. Even if simulations are run with similar input files, the use of different simulation engines could give different free energy results. As part of a collaborative effort, the implementation details of AMBER, GROMACS, SOMD and CHARMM simulation codes were studied and free energy protocols for each software were validated to converge towards a reproducibility limit of about 0.20 kcal.mol-1 for hydration free energies of small organic molecules. Following, new simulation methods for the estimation of lipophilicity coefficients (log P and log D) for drug like molecules were developed and validated. log P values were computed for a dataset of 5 molecules with increasing fluorination level. Predictions were in line with the experimental measures and the simulations also allowed new insights into the water-solute interactions that drive the partitioning process. Then, as part of the SAMPL5 challenge, log D values for 53 drug-like molecules were computed. In this context two different simulation models were derived in order to take into account the presence of protonated species. The results were encouraging but also highlighted limits in alchemical free energy modelling. As an additional task of the SAMPL5 contest, three different protocols were validated for predicting absolute binding affinities for 22 host-guest systems. The first model yielded a free energy of binding based on free energy changes in solvated and complex phase; the second added the long range dispersion correction to the previous model; the third one used a standard state correction term. All three protocols were among the top-ranked submission in SAMPL5, with a correlation coefficient R2 of about 0.7 against experimental data. Finally, the origins and magnitude of the finite size artefacts in alchemical free energy calculations were investigated. Finite size artefacts are especially predominant in calculations that involve changes in the net-charge of a solute. A new correction scheme was devised for the Barker Watts Reaction Field approach and compared with the literature. Hydration free energy calculations on simple ionic species were carried out to validate the consistency of the scheme and the approach was further extended to host-guest binding affinities predictions

Separation of heat and charge currents for boosted thermoelectric conversion

In a multi-terminal device the (electronic) heat and charge currents can follow different paths. In this paper we introduce and analyse a class of multi-terminal devices where this property is pushed to its extreme limits, with charge $and$ heat currents flowing in different reservoirs. After introducing the main characteristics of such $heat-charge$ $current$ $separation$ regime we show how to realise it in a multi-terminal device with normal and superconducting leads. We demonstrate that this regime allows to control independently heat and charge flows and to greatly enhance thermoelectric performances at low temperatures. We analyse in details a three-terminal setup involving a superconducting lead, a normal lead and a voltage probe. For a generic scattering region we show that in the regime of heat-charge current separation both the power factor and the figure of merit $ZT$ are highly increased with respect to a standard two-terminal system. These results are confirmed for the specific case of a system consisting of three coupled quantum dots.Comment: 12 pages, 8 figure

Photoinduced Millisecond Switching Kinetics in the GFPMut2 E222Q Mutant

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Reproducibility of Free Energy Calculations Across Different Molecular Simulation Software

<div> <div> <div> <p>Alchemical free energy calculations are an increasingly important modern simulation technique. Contemporary molecular simulation software such as AMBER, CHARMM, GROMACS and SOMD include support for the method. Implementation details vary among those codes but users expect reliability and reproducibility, i.e. for a given molec- ular model and set of forcefield parameters, comparable free energy should be obtained within statistical bounds regardless of the code used. Relative alchemical free energy (RAFE) simulation is increasingly used to support molecule discovery projects, yet the reproducibility of the methodology has been less well tested than its absolute counter- part. Here we present RAFE calculations of hydration free energies for a set of small organic molecules and demonstrate that free energies can be reproduced to within about 0.2 kcal/mol with aforementioned codes. Achieving this level of reproducibility requires considerable attention to detail and package–specific simulation protocols, and no uni- versally applicable protocol emerges. The benchmarks and protocols reported here should be useful for the community to validate new and future versions of software for free energy calculations.</p></div></div></div

Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors

Hit-to-lead virtual screening frequently relies on a cascade of computational methods that starts with rapid calculations applied to a large number of compounds and ends with more expensive computations restricted to a subset of compounds that passed initial filters. This work focuses on set up protocols for alchemical free energy (AFE) scoring in the context of a Docking–MM/PBSA–AFE cascade. A dataset of 15 congeneric inhibitors of the ACK1 protein was used to evaluate the performance of AFE set up protocols that varied in the steps taken to prepare input files (using previously docked and best scored poses, manual selection of poses, manual placement of binding site water molecules). The main finding is that use of knowledge derived from X-ray structures to model binding modes, together with the manual placement of a bridging water molecule, improves the R2 from 0.45 ± 0.06 to 0.76 ± 0.02 and decreases the mean unsigned error from 2.11 ± 0.08 to 1.24 ± 0.04 kcal mol-1. By contrast a brute force automated protocol that increased the sampling time ten-fold lead to little improvements in accuracy. Besides, it is shown that for the present dataset hysteresis can be used to flag poses that need further attention even without prior knowledge of experimental binding affinitiesPeer ReviewedPostprint (published version

Blinded predictions of distribution coefficients in the SAMPL5 challenge

In the context of the SAMPL5 challenge water-cyclohexane distribution coefficients for 53 drug-like molecules were predicted. Four different models based on molecular dynamics free energy calculations were tested. All models initially assumed only one chemical state present in aqueous or organic phases. Model A is based on results from an alchemical annihilation scheme; model B adds a long range correction for the Lennard Jones potentials to model A; model C adds charging free energy corrections; model D applies the charging correction from model C to ionizable species only. Model A and B perform better in terms of mean-unsigned error ([Formula: see text] D units − 95 % confidence interval) and determination coefficient [Formula: see text] , while charging corrections lead to poorer results with model D ([Formula: see text] and [Formula: see text] ). Because overall errors were large, a retrospective analysis that allowed co-existence of ionisable and neutral species of a molecule in aqueous phase was investigated. This considerably reduced systematic errors ([Formula: see text] and [Formula: see text] ). Overall accurate [Formula: see text] predictions for drug-like molecules that may adopt multiple tautomers and charge states proved difficult, indicating a need for methodological advances to enable satisfactory treatment by explicit-solvent molecular simulations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10822-016-9969-1) contains supplementary material, which is available to authorized users

Effect of a quality improvement program on compliance to the sepsis bundle in non-ICU patients: a multicenter prospective before and after cohort study

ObjectiveSepsis and septic shock are major challenges and economic burdens to healthcare, impacting millions of people globally and representing significant causes of mortality. Recently, a large number of quality improvement programs focused on sepsis resuscitation bundles have been instituted worldwide. These educational initiatives have been shown to be associated with improvements in clinical outcomes. We aimed to evaluate the impact of a multi-faceted quality implementing program (QIP) on the compliance of a “simplified 1-h bundle” (Sepsis 6) and hospital mortality of severe sepsis and septic shock patients out of the intensive care unit (ICU).MethodsEmergency departments (EDs) and medical wards (MWs) of 12 academic and non-academic hospitals in the Lombardy region (Northern Italy) were involved in a multi-faceted QIP, which included educational and organizational interventions. Patients with a clinical diagnosis of severe sepsis or septic shock according to the Sepsis-2 criteria were enrolled in two different periods: from May 2011 to November 2011 (before-QIP cohort) and from August 2012 to June 2013 (after-QIP cohort).Measurements and main resultsThe effect of QIP on bundle compliance and hospital mortality was evaluated in a before–after analysis. We enrolled 467 patients in the before-QIP group and 656 in the after-QIP group. At the time of enrollment, septic shock was diagnosed in 50% of patients, similarly between the two periods. In the after-QIP group, we observed increased compliance to the “simplified rapid (1 h) intervention bundle” (the Sepsis 6 bundle – S6) at three time-points evaluated (1 h, 13.7 to 18.7%, p = 0.018, 3 h, 37.1 to 48.0%, p = 0.013, overall study period, 46.2 to 57.9%, p &lt; 0.001). We then analyzed compliance with S6 and hospital mortality in the before- and after-QIP periods, stratifying the two patients’ cohorts by admission characteristics. Adherence to the S6 bundle was increased in patients with severe sepsis in the absence of shock, in patients with serum lactate &lt;4.0 mmol/L, and in patients with hypotension at the time of enrollment, regardless of the type of admission (from EDs or MWs). Subsequently, in an observational analysis, we also investigated the relation between bundle compliance and hospital mortality by logistic regression. In the after-QIP cohort, we observed a lower in-hospital mortality than that observed in the before-QIP cohort. This finding was reported in subgroups where a higher adherence to the S6 bundle in the after-QIP period was found. After adjustment for confounders, the QIP appeared to be independently associated with a significant improvement in hospital mortality. Among the single S6 procedures applied within the first hour of sepsis diagnosis, compliance with blood culture and antibiotic therapy appeared significantly associated with reduced in-hospital mortality.ConclusionA multi-faceted QIP aimed at promoting an early simplified bundle of care for the management of septic patients out of the ICU was associated with improved compliance with sepsis bundles and lower in-hospital mortality

Observation of a Charmed Baryon Decaying to D0p at a Mass Near 2.94 GeV/c2

A search for charmed baryons decaying to D 0 p reveals two states: the Λ c ( 2880 ) + baryon and a previously unobserved state at a mass of [ 2939.8 ± 1.3 ( stat ) ± 1.0 ( syst ) ]     MeV / c 2 and with an intrinsic width of [ 17.5 ± 5.2 ( stat ) ± 5.9 ( syst ) ]     MeV . Consistent and significant signals are observed for the K − π + and K − π + π − π + decay modes of the D 0 in 287     fb − 1 annihilation data recorded by the BABAR detector at a center-of-mass energy of 10.58 GeV. There is no evidence in the D + p spectrum of doubly charged partners. The mass and intrinsic width of the Λ c ( 2880 ) + baryon and relative yield of the two baryons are also measured