RESUMO
Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumour types, including melanoma, glioma, leukaemia and cardiac angiosarcoma. We sequenced all coding exons of the POT1 gene in 2928 European-descent melanoma cases and 3298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop-gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations. We determine that POT1 coding variants are a minor contributor to melanoma burden in the general population, with only about 0.5% of melanoma cases carrying germline pathogenic variants in this gene, but should be screened in individuals with a strong family history of melanoma and/or multiple malignancies.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Neoplasias Cutâneas/genética , Complexo Shelterina , Proteínas de Ligação a Telômeros/genética , Telômero/metabolismo , Estudos de Casos e Controles , Melanoma Maligno CutâneoRESUMO
We present a new development in quantum mechanics/molecular mechanics (QM/MM) methods by replacing conventional MM models with data-driven many-body (MB) representations rigorously derived from high-level QM calculations. The new QM/MM approach builds on top of mutually polarizable QM/MM schemes developed for polarizable force fields with inducible dipoles and uses permutationally invariant polynomials to effectively account for quantum-mechanical contributions (e.g., exchange-repulsion and charge transfer and penetration) that are difficult to describe by classical expressions adopted by conventional MM models. Using the many-body MB-pol and MB-DFT potential energy functions for water, which include explicit two-body and three-body terms fitted to reproduce the corresponding CCSD(T) and PBE0 two-body and three-body energies for water, we demonstrate a smooth energetic transition as molecules are transferred between QM and MM regions, without the need of a transition layer. By effectively elevating the accuracy of both the MM region and the QM/MM interface to that of the QM region, the new QM/MB-MM approach achieves an accuracy comparable to that obtained with a fully QM treatment of the entire system.
RESUMO
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 ALKBH7, 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.
Assuntos
Enzimas AlkB/genética , Ácidos Cetoglutáricos/química , Proteínas Mitocondriais/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Negro ou Afro-Americano/estatística & dados numéricos , Sítios de Ligação , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Ativação Enzimática , Marcadores Genéticos/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Simulação de Dinâmica Molecular , Oxigênio/química , Prevalência , Ligação Proteica , Fatores de Risco , Especificidade por Substrato , Estados Unidos/epidemiologia , Estados Unidos/etnologiaRESUMO
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.