Modeling Molecular Interactions in Water: From Pairwise to Many-Body Potential Energy Functions.

Almost 50 years have passed from the first computer simulations of water, and a large number of molecular models have been proposed since then to elucidate the unique behavior of water across different phases. In this article, we review the recent progress in the development of analytical potential energy functions that aim at correctly representing many-body effects. Starting from the many-body expansion of the interaction energy, specific focus is on different classes of potential energy functions built upon a hierarchy of approximations and on their ability to accurately reproduce reference data obtained from state-of-the-art electronic structure calculations and experimental measurements. We show that most recent potential energy functions, which include explicit short-range representations of two-body and three-body effects along with a physically correct description of many-body effects at all distances, predict the properties of water from the gas to the condensed phase with unprecedented accuracy, thus opening the door to the long-sought "universal model" capable of describing the behavior of water under different conditions and in different environments

Population-based analysis of POT1 variants in a cutaneous melanoma case–control cohort

Article describes how pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumor types, including melanoma, glioma, leukemia and cardiac angiosarcoma. The authors sequenced all coding exons of the POT1 gene in 2928 European-descent melanoma cases and 3298 controls, identifying 43 protein-changing genetic variants

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Computational investigation of O₂ diffusion through an intra-molecular tunnel in AlkB; influence of polarization on O₂ transport

This article discusses the use of computational simulations to investigate possible migration pathways inside AlkB for O₂ molecules

Insight into wild-type and T1372E TET2-mediated 5hmC oxidation using ab initio QM/MM calculations

This article studies the catalytic mechanism of oxidation of 5hmC to 5fC by WT and T1372E TET2 using an ab initio quantum mechanical/molecular mechanical (QM/MM) approach

ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding

<div><p>The search for prostate cancer biomarkers has received increased attention and several DNA repair related enzymes have been linked to this dysfunction. Here we report a targeted search for single nucleotide polymorphisms (SNPs) and functional impact characterization of human ALKBH family dioxygenases related to prostate cancer. Our results uncovered a SNP of <i>ALKBH7</i>, rs7540, which is associated with prostate cancer disease in a statistically significantly manner in two separate cohorts, and maintained in African American men. Comparisons of molecular dynamics (MD) simulations on the wild-type and variant protein structures indicate that the resulting alteration in the enzyme induces a significant structural change that reduces ALKBH7’s ability to bind its cosubstrate. Experimental spectroscopy studies with purified proteins validate our MD predictions and corroborate the conclusion that this cancer-associated mutation affects productive cosubstrate binding in ALKBH7.</p></div

Difference absorption spectra of WT ALKBH7 and its R191Q variant.

<p>The spectra of the anaerobic proteins (0.3 mM) were recorded in the presence of 2 mM α-kg and 100 μM Fe(II). The difference spectra were obtained by subtracting the spectra for proteins with α-kg, but without the metal. <b>A</b>, WT ALKBH7; <b>B</b>, R191Q ALKBH7.</p

SNPs of <i>ALKBH</i> family genes with significant association (p ≤ 0.05) with prostate cancer phenotype.

<p>SNPs of <i>ALKBH</i> family genes with significant association (p ≤ 0.05) with prostate cancer phenotype.</p

Structural and dynamic comparison between WT and R191Q ALKBH7 with bound α-kg.

<p><b>a,</b> Overlay of representative structures for WT (gray) and R191Q mutant (yellow) forms of ALKBH7. Active site residues and α-kg as well as the site undergoing substitution are displayed (licorice). <b>b,</b> 180 degree rotation and close-up of the substituted site. <b>c,</b> 90 degree rotation and close-up of the active site, with each relevant active site residue and α-kg labeled. Dashed lines in gray represent the original bonds to the metal ion in the crystal structure, and dashed lines in orange represent the new bonds to the metal ion near the end of the trajectory for the variant protein. <b>d,</b> Correlation difference for each residue in the WT protein with respect to the R191Q variant mapped onto the protein structure using the mutation site as the reference. <b>e,</b> Distance analysis for key residues in the SNP variant and active sites (with respect to their centers of mass) throughout the simulation trajectory.</p