Conformational entropy in molecular recognition by proteins

Molecular recognition by proteins is fundamental to almost every biological process, particularly the protein associations underlying cellular signal transduction. Understanding the basis for protein-protein interactions requires the full characterization of the thermodynamics of their association. Historically it has been virtually impossible to experimentally estimate changes in protein conformational entropy, a potentially important component of the free energy of protein association. However, nuclear magnetic resonance spectroscopy has emerged as a powerful tool for characterizing the dynamics of proteins. Here we employ changes in conformational dynamics as a proxy for corresponding changes in conformational entropy. We find that the change in internal dynamics of the protein calmodulin varies significantly on binding a variety of target domains. Surprisingly, the apparent change in the corresponding conformational entropy is linearly related to the change in the overall binding entropy. This indicates that changes in protein conformational entropy can contribute significantly to the free energy of protein-ligand association.     

Ediacaran oxidation and biotic evolution

The link between the radiation of various lineages of eukaryotes in the latest Proterozoic and massive environmental changes--oxygenation, global ice ages and bolide impact--is the focus of much research interest. Fike et al. use carbon and sulphur isotope-chemostratigraphic data from Oman to propose three stages of oxidation in the Ediacaran oceans, and link the second and third stages to eukaryote diversification. The second stage, signalled by strongly 13C-depleted sedimentary carbonates (the 'Shuram excursion'), is believed to result from oxidation of a large, deep-ocean reservoir of organic carbon. Fike et al. use our data to assert that a correlative carbon isotope excursion in Australia coincided with the initial diversification of acanthomorphic acritarchs. Peak diversity is claimed to have coincided with subsequent deposition of 13C-enriched carbonate and the third oxidation stage. However, the authors seem to have misinterpreted our data, which instead indicate that diversification significantly preceded the Shuram excursion; this weakens their argument for a link between the inferred oxidation events and eukaryote evolution.     

Detectable clonal mosaicism from birth to old age and its relationship to cancer

We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5-10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2-3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6-18).