Superposition-Enhanced Estimation of Optimal Temperature Spacings for Parallel Tempering Simulations.

Effective parallel tempering simulations rely crucially on a properly chosen sequence of temperatures. While it is desirable to achieve a uniform exchange acceptance rate across neighboring replicas, finding a set of temperatures that achieves this end is often a difficult task, in particular for systems undergoing phase transitions. Here we present a method for determination of optimal replica spacings, which is based upon knowledge of local minima in the potential energy landscape. Working within the harmonic superposition approximation, we derive an analytic expression for the parallel tempering acceptance rate as a function of the replica temperatures. For a particular system and a given database of minima, we show how this expression can be used to determine optimal temperatures that achieve a desired uniform acceptance rate. We test our strategy for two atomic clusters that exhibit broken ergodicity, demonstrating that our method achieves uniform acceptance as well as significant efficiency gains.This project was funded by EPSRC Grant EP/I001352/1 and the ERC

Intrinsically disordered energy landscapes.

Analysis of an intrinsically disordered protein (IDP) reveals an underlying multifunnel structure for the energy landscape. We suggest that such 'intrinsically disordered' landscapes, with a number of very different competing low-energy structures, are likely to characterise IDPs, and provide a useful way to address their properties. In particular, IDPs are present in many cellular protein interaction networks, and several questions arise regarding how they bind to partners. Are conformations resembling the bound structure selected for binding, or does further folding occur on binding the partner in a induced-fit fashion? We focus on the p53 upregulated modulator of apoptosis (PUMA) protein, which adopts an α-helical conformation when bound to its partner, and is involved in the activation of apoptosis. Recent experimental evidence shows that folding is not necessary for binding, and supports an induced-fit mechanism. Using a variety of computational approaches we deduce the molecular mechanism behind the instability of the PUMA peptide as a helix in isolation. We find significant barriers between partially folded states and the helix. Our results show that the favoured conformations are molten-globule like, stabilised by charged and hydrophobic contacts, with structures resembling the bound state relatively unpopulated in equilibrium.The authors thank Prof. Jane Clarke, Dr. Chris Whittleston, Dr. Joanne Carr, Dr. Iskra Staneva and Dr. David de Sancho for helpful discussions. Y.C. and A.J.B. acknowledge funding from the EPSRC grant number EP/I001352/1, D.C. gratefully acknowledges the Cambridge Commonwealth European and International Trust for financial support and D.J.W. the ERC for an Advanced Grant.This is the final version. It was first published by NPG at http://www.nature.com/srep/2015/150522/srep10386/full/srep10386.html?WT.ec_id=SREP-639%2C638-20150526#abstract

The problem of racemization in drug discovery and tools to predict it

Introduction: Racemization has long been an ignored risk in drug development, probably because of a lack of convenient access to good tools for its detection and an absence of methods to predict racemization risk. As a result, the potential effects of racemization have been systematically underestimated. Areas covered: Herein, the potential effects of racemization are discussed through a review of drugs for which activity and side effects for both enantiomers are known. Subsequently, drugs known to racemize are discussed and the authors review methods to predict racemization risk. Application of a method quantitatively predicting racemization risk to databases of compounds from the medicinal chemistry literature shows that success in clinical trials is negatively correlated with racemization risk. Expert opinion: It is envisioned that a quantitative method of predicting racemization risk will remove a blind spot from the drug development pipeline. Removal of the blind spot will make drug development more efficient and result in less late-stage attrition of the drug pipeline

Energy landscapes for a machine learning application to series data

Methods developed to explore and characterise potential energy landscapes are applied to the corresponding landscapes obtained from optimisation of a cost function in machine learning. We consider neural network predictions for the outcome of local geometry optimisation in a triatomic cluster, where four distinct local minima exist. The accuracy of the predictions is compared for fits using data from single and multiple points in the series of atomic configurations resulting from local geometry optimisation and for alternative neural networks. The machine learning solution landscapes are visualised using disconnectivity graphs, and signatures in the effective heat capacity are analysed in terms of distributions of local minima and their properties.We gratefully acknowledge funding from the EPSRC and the ERC

Hazy with a chance of star spots: constraining the atmosphere of the young planet, K2-33b

Although all-sky surveys have led to the discovery of dozens of young planets, little is known about their atmospheres. Here, we present multi-wavelength transit data for the super Neptune-sized exoplanet, K2-33b -- the youngest (~10 Myr) transiting exoplanet to-date. We combined photometric observations of K2-33 covering a total of 33 transits spanning >2 years, taken from K2, MEarth, Hubble, and Spitzer. The transit photometry spanned from the optical to the near-infrared (0.6-4.5$\mu$m), enabling us to construct a transmission spectrum of the planet. We find that the optical transit depths are nearly a factor of two deeper than those from the near-infrared. This difference holds across multiple datasets taken over years, ruling out issues of data analysis and unconstrained systematics. Surface inhomogeneities on the young star can reproduce some of the difference, but required spot coverage fractions (>60%) are ruled out by the observed stellar spectrum(<20%). We find a better fit to the transmission spectrum using photochemical hazes, which were predicted to be strong in young, moderate-temperature, and large-radius planets like K2-33b. A tholin haze with CO as the dominant gaseous carbon carrier in the atmosphere can reasonably reproduce the data with small or no stellar surface inhomogeneities, consistent with the stellar spectrum. The HST data quality is insufficient for the detection of any molecular features. More observations would be required to fully characterize the hazes and spot properties and confirm the presence of CO suggested by current data.Comment: Accepted to AJ. 26 pages, 14 figures, 6 table

Hazy with a Chance of Star Spots: Constraining the Atmosphere of Young Planet K2-33b

Although all-sky surveys have led to the discovery of dozens of young planets, little is known about their atmospheres. Here, we present multiwavelength transit data for the super-Neptune sized exoplanet, K2-33b-the youngest (~10 Myr) transiting exoplanet to date. We combined photometric observations of K2-33 covering a total of 33 transits spanning >2 yr, taken from K2, MEarth, the Hubble Space Telescope (HST), and Spitzer. The transit photometry spanned from the optical to the near-infrared (0.6-4.5 μm), enabling us to construct a transmission spectrum of the planet. We find that the optical transit depths are nearly a factor of 2 deeper than those from the near-infrared. This difference holds across multiple data sets taken over years, ruling out issues of data analysis and unconstrained systematics. Surface inhomogeneities on the young star can reproduce some of the difference, but required spot coverage fractions (>60%) are ruled out by the observed stellar spectrum (<20%). We find a better fit to the transmission spectrum using photochemical hazes, which were predicted to be strong in young, moderate-temperature, and large-radius planets like K2-33b. A tholin haze with CO as the dominant gaseous carbon carrier in the atmosphere can reasonably reproduce the data with small or no stellar surface inhomogeneities, consistent with the stellar spectrum. The HST data quality is insufficient for the detection of any molecular features. More observations would be required to fully characterize the hazes and spot properties and confirm the presence of CO suggested by current data

Isolation, small population size, and management influence inbreeding and reduced genetic variation in K’gari dingoes

Small island populations are vulnerable to genetic decline via demographic and environmental stochasticity. In the absence of immigration, founder effects, inbreeding and genetic drift are likely to contribute to local extinction risk. Management actions may also have a greater impact on small, closed populations. The demographic and social characteristics of a species can, however, delay the impact of threats. K’gari, a ~ 1 660 km2 island off the Australian east coast and UNESCO World Heritage Site (Fraser Island 1842–2023), supports an isolated population of approximately 70–200 dingoes that represent an ideal opportunity to explore the small island paradigm. To examine temporal and spatial patterns of genetic diversity in this population we analysed single nucleotide polymorphism (SNP) genotype data (72 454 SNPS) for 112 K’gari dingoes collected over a 25-year period (1996 to 2020). Genetic diversity was lower in K’gari dingoes than mainland dingoes at the earliest time point in our study and declined significantly following a management cull in 2001. We did not find any spatial genetic patterns on the island, suggesting high levels of genetic connectivity between socially discrete packs. This connectivity, combined with the social structure and behaviour of dingoes, may act in concert to buffer the population from the impacts of genetic drift in the short term. Nevertheless, a general decline in genetic variation via inbreeding and drift has occurred over the past 20 years which we suggest should be considered in any future management planning for the population. Monitoring patterns of genetic variation, together with a clearer understanding of the social ecology of K’gari dingoes, will aid in the development of measurable genetic targets set over ecologically meaningful timelines, and help ensure continued survival of this culturally important population

Racemisation in chemistry and biology

The two enantiomers of a compound often have profoundly different biological properties and so their liability to racemisation in aqueous solutions is an important piece of information. We have reviewed the available data concerning the process of racemisation in vivo, in the presence biological molecules (e.g. racemase enzymes, serum albumin, cofactors and derivatives) and under purely chemical but aqueous conditions (acid, base and other aqueous systems). Mechanistic studies are described critically in light of reported kinetic data. The types of experimental measurement that can be used to effectively determine rate constants of racemisation in various conditions are discussed and the data they provide is summarised. The proposed origins of enzymatic racemisation are presented and suggest ways to promote the process that are different from processes taking place in bulk water. Experimental and computational studies that provide understanding and quantitative predictions of racemisation risk are also presented