Structural Biology by NMR: Structure, Dynamics, and Interactions

The function of bio-macromolecules is determined by both their 3D structure and conformational dynamics. These molecules are inherently flexible systems displaying a broad range of dynamics on time-scales from picoseconds to seconds. Nuclear Magnetic Resonance (NMR) spectroscopy has emerged as the method of choice for studying both protein structure and dynamics in solution. Typically, NMR experiments are sensitive both to structural features and to dynamics, and hence the measured data contain information on both. Despite major progress in both experimental approaches and computational methods, obtaining a consistent view of structure and dynamics from experimental NMR data remains a challenge. Molecular dynamics simulations have emerged as an indispensable tool in the analysis of NMR data

Striking HIV-1 Entry by Targeting HIV-1 gp41. But, Where Should We Target?

HIV-1 gp41 facilitates the viral fusion through a conformational switch involving the association of three C-terminal helices along the conserved hydrophobic grooves of three N-terminal helices coiled-coil. The control of these structural rearrangements is thought to be central to HIV-1 entry and, therefore, different strategies of intervention are being developed. Herewith, we describe a procedure to simulate the folding of an HIV-1 gp41 simplified model. This procedure is based on the construction of plausible conformational pathways, which describe protein transition between non-fusogenic and fusogenic conformations. The calculation of the paths started with 100 molecular dynamics simulations of the non-fusogenic conformation, which were found to converge to different intermediate states. Those presenting defined criteria were selected for separate targeted molecular dynamics simulations, subjected to a force constant imposing a movement towards the gp41 fusogenic conformation. Despite significant diversity, a preferred sequence of events emerged when the simulations were analyzed in terms of the formation, breakage and evolution of the contacts. We pointed out 29 residues as the most relevant for the movement of gp41; also, 2696 possible interactions were reduced to only 48 major interactions, which reveals the efficiency of the method. The analysis of the evolution of the main interactions lead to the detection of four main behaviors for those contacts: stable, increasing, decreasing and repulsive interactions. Altogether, these results suggest a specific small cavity of the HIV-1 gp41 hydrophobic groove as the preferred target to small molecules

Vitamin D status is inversely associated with markers of risk for type 2 diabetes: A population based study in Victoria, Australia

A growing body of evidence suggests a protective role of Vitamin D on the risk of type 2 diabetes mellitus (T2DM). We investigated this relationship in a population sample from one Australian state. The data of 3,393 Australian adults aged 18±75 years who participated in the 2009±2010 Victorian Health Monitor survey was analyzed. Socio-demographic information, biomedical variables, and dietary intakes were collected and fasting blood samples were analyzed for 25, hydroxycholecalciferol (25OHD), HbA1c, fasting plasma glucose (FPG), and lipid profiles. Logistic regression analyses were used to evaluate the association between tertiles of serum 25OHD and categories of FPG (<5.6 mmol/L vs. 5.6±6.9 mmol/L), and HbA1c (<5.7% vs. 5.7±6.4%). After adjusting for social, dietary, biomedical and metabolic syndrome (MetS) components (waist circumference, HDL cholesterol, triglycerides, and blood pressure), every 10 nmol/L increment in serum 25OHD significantly reduced the adjusted odds ratio (AOR) of a higher FPG [AOR 0.91, (0.86, 0.97); p = 0.002] and a higher HbA1c [AOR 0.94, (0.90, 0.98); p = 0.009]. Analysis by tertiles of 25OHD indicated that after adjustment for socio-demographic and dietary variables, those with high 25OHD (65±204 nmol/L) had reduced odds of a higher FPG [AOR 0.60, (0.43, 0.83); p = 0.008] as well as higher HbA1c [AOR 0.67, (0.53, 0.85); p = 0.005] compared to the lowest 25OHD (10±44 nmol/L) tertile. On final adjustment for other components of MetS, those in the highest tertile of 25OHD had significantly reduced odds of higher FPG [AOR 0.61, (0.44, 0.84); p = 0.011] and of higher HbA1c [AOR 0.74, (0.58, 0.93); p = 0.041] vs. low 25OHD tertile. Overall, the data support a direct, protective effect of higher 25OHD on FPG and HbA1c; two criteria for assessment of risk of T2DM

Early Jurassic North Atlantic sea-surface temperatures from TEX86 palaeothermometry

Early Jurassic marine palaeotemperatures have been typically quantified by oxygen-isotope palaeothermometry of benthic and nektonic carbonate and phosphatic macrofossils. However, records of Early Jurassic sea-surface temperatures (SSTs) that can be directly compared with General Circulation Model (GCM) simulations of past climates are currently unavailable. The TEX86 SST proxy is based upon the relative abundance of glycerol dialkyl glycerol tetraethers (GDGTs) preserved in organic-carbon-bearing sediments. This proxy has been used extensively on Cretaceous and Cenozoic materials and, in one study, Middle and Upper Jurassic sediments. Here TEX86 is applied, for the first time, to Lower Jurassic (Sinemurian–Pliensbachian) sediments cored at Deep Sea Drilling Project Site 547 in the North Atlantic. The abundance of GDGTs in these sediments is very low, despite biomarker and Rock-Eval data suggesting that thermal maturity is, generally, low. Sea-floor oxygenation and a high input of reworked terrestrially sourced organic matter may explain the low concentrations. For samples from which it was possible to quantify the relative abundance of GDGTs, TEX86 values range from 0.78 to 0.88, equating to SSTs in excess of >28˚C. These temperatures are broadly comparable with new GCM simulations of the Sinemurian and Pliensbachian stages and support the general view of a predominantly warm climate. The new proxy data suggest that, under favourable geological conditions, it is possible to extend the record of TEX86-based SSTs back into the Early Jurassic

Early Jurassic North Atlantic sea-surface temperatures from TEX86 palaeothermometry

Early Jurassic marine palaeotemperatures have been typically quantified by oxygen-isotope palaeothermometry of benthic and nektonic carbonate and phosphatic macrofossils. However, records of Early Jurassic sea-surface temperatures (SSTs) that can be directly compared with General Circulation Model (GCM) simulations of past climates are currently unavailable. The TEX86 SST proxy is based upon the relative abundance of glycerol dialkyl glycerol tetraethers (GDGTs) preserved in organic-carbon-bearing sediments. This proxy has been used extensively on Cretaceous and Cenozoic materials and, in one study, Middle and Upper Jurassic sediments. Here TEX86 is applied, for the first time, to Lower Jurassic (Sinemurian–Pliensbachian) sediments cored at Deep Sea Drilling Project Site 547 in the North Atlantic. The abundance of GDGTs in these sediments is very low, despite biomarker and Rock-Eval data suggesting that thermal maturity is, generally, low. Sea-floor oxygenation and a high input of reworked terrestrially sourced organic matter may explain the low concentrations. For samples from which it was possible to quantify the relative abundance of GDGTs, TEX86 values range from 0.78 to 0.88, equating to SSTs in excess of >28˚C. These temperatures are broadly comparable with new GCM simulations of the Sinemurian and Pliensbachian stages and support the general view of a predominantly warm climate. The new proxy data suggest that, under favourable geological conditions, it is possible to extend the record of TEX86-based SSTs back into the Early Jurassic

Crocodylian diversity peak and extinction in the late Cenozoic of the northern Neotropics

Northern South America and South East Asia are today’s hotspots of crocodylian diversity with up to six (mainly alligatorid) and four (mainly crocodylid) living species respectively, of which usually no more than two or three occur sympatrically. In contrast, during the late Miocene, 14 species existed in South America. Here we show a diversity peak in sympatric occurrence of at least seven species, based on detailed stratigraphic sequence sampling and correlation, involving four geological formations from the middle Miocene to the Pliocene, and on the discovery of two new species and a new occurrence. This degree of crocodylian sympatry is unique in the world and shows that at least several members of Alligatoroidea and Gavialoidea coexisted. By the Pliocene, all these species became extinct, and their extinction was probably related to hydrographic changes linked to the Andean uplift. The extant fauna is first recorded with the oldest Crocodylus species from South America.Fil: Scheyer, T. M.. Universitat Zurich; SuizaFil: Aguilera, Oscar Alberto. Universidade Federal Fluminense; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Delfino, M.. Universita di Torino; Italia. Universitat Autonoma de Barcelona; EspañaFil: Fortier, D. C.. Universidade Federal do Rio Grande do Sul; BrasilFil: Carlini, Alfredo Armando. Universidad Nacional de la Plata. Facultad de Ciencias Naturales y Museo. División Paleontología Vertebrados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sanchez, R.. Smithsonian Tropical Research Institute; PanamáFil: Carrillo Briceño, J. D.. Alcaldía Bolivariana del Municipio Urumaco; VenezuelaFil: Quiroz, L.. University Of Saskatchewan; CanadáFil: Sánchez Villagra, M. R.. Universitat Zurich; Suiz