The change in binding energy on moving from the reactant state to the transition state is the central issue of the origin of enzyme catalysis. Warshel et al analyze the finding of a major ...electrostatic contribution to catalysis and shown to reflect the preorganized polar environment of the enzyme active site.
The new empirical rules for protein pKa predictions implemented in the PROPKA3.0 software package (Olsson et al. J. Chem. Theory Comput.2010, 7, 525-537) have been extended to the prediction of pKa ...shifts of active site residues and ionizable ligand groups in protein-ligand complexes. We present new algorithms that allow pKa shifts due to inductive (i.e., covalently coupled) intraligand interactions, as well as noncovalently coupled interligand interactions in multiligand complexes, to be included in the prediction. The number of different ligand chemical groups that are automatically recognized has been increased to 18, and the general implementation has been changed so that new functional groups can be added easily by the user, aided by a new and more general protonation scheme. Except for a few cases, the new algorithms in PROPKA3.1 are found to yield results similar to or better than those obtained with PROPKA2.0 (Bas et al. Proteins: Struct., Funct., Bioinf.2008, 73, 765-783). Finally, we present a novel algorithm that identifies noncovalently coupled ionizable groups, where pKa prediction may be especially difficult. This is a general improvement to PROPKA and is applied to proteins with and without ligands.
Charge states of ionizable residues in proteins determine their pH-dependent properties through their pKa values. Thus, various theoretical methods to determine ionization constants of residues in ...biological systems have been developed. One of the more widely used approaches for predicting pKa values in proteins is the PROPKA program, which provides convenient structural rationalization of the predicted pKa values without any additional calculations.
The PROPKA Graphical User Interface (GUI) is a new tool for studying the pH-dependent properties of proteins such as charge and stabilization energy. It facilitates a quantitative analysis of pKa values of ionizable residues together with their structural determinants by providing a direct link between the pKa data, predicted by the PROPKA calculations, and the structure via the Visual Molecular Dynamics (VMD) program. The GUI also calculates contributions to the pH-dependent unfolding free energy at a given pH for each ionizable group in the protein. Moreover, the PROPKA-computed pKa values or energy contributions of the ionizable residues in question can be displayed interactively. The PROPKA GUI can also be used for comparing pH-dependent properties of more than one structure at the same time.
The GUI considerably extends the analysis and validation possibilities of the PROPKA approach. The PROPKA GUI can conveniently be used to investigate ionizable groups, and their interactions, of residues with significantly perturbed pKa values or residues that contribute to the stabilization energy the most. Charge-dependent properties can be studied either for a single protein or simultaneously with other homologous structures, which makes it a helpful tool, for instance, in protein design studies or structure-based function predictions. The GUI is implemented as a Tcl/Tk plug-in for VMD, and can be obtained online at http://propka.ki.ku.dk/~luca/wiki/index.php/GUI_Web.
The evolution of female promiscuity poses an intriguing problem as benefits of mating with multiple males often have to arise via indirect, genetic, effects. Studies on birds have documented that ...multiple paternity is common in natural populations but strong evidence for selection via female benefits is lacking. In an attempt to evaluate the evidence more broadly, we review studies of multiple paternity in natural populations of all major groups of nonavian reptiles. Multiple paternity has been documented in all species investigated so far and commonly exists in over 50% of clutches, with particularly high levels in snakes and lizards. Marine turtles and lizards with prolonged pair‐bonding have relatively low levels of multiple paternity but levels are nevertheless higher than in many vertebrates with parental care. There is no evidence that high levels of polyandry are driven by direct benefits to females and the evidence that multiple paternity arises from indirect genetic benefits is weak. Instead, we argue that the most parsimonious explanation for patterns of multiple paternity is that it represents the combined effect of mate‐encounter frequency and conflict over mating rates between males and females driven by large male benefits and relatively small female costs, with only weak selection via indirect benefits. A crucial step for researchers is to move from correlative approaches to experimental tests of assumptions and predictions of theory under natural settings, using a combination of molecular techniques and behavioural observations.
Ectothermic telomeres: it's time they came in from the cold Olsson, Mats; Wapstra, Erik; Friesen, Christopher
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
03/2018, Letnik:
373, Številka:
1741
Journal Article
Recenzirano
Odprti dostop
We review the evolutionary ecology and genetics of telomeres in taxa that cannot elevate their body temperature to a preferred level through metabolism but do so by basking or seeking out a warm ...environment. This group of organisms contains all living things on earth, apart from birds and mammals. One reason for our interest in this synthetic group is the argument that high, stable body temperature increases the risk of malignant tumours if long, telomerase-restored telomeres make cells ‘live forever’. If this holds true, ectotherms should have significantly lower cancer frequencies. We discuss to what degree there is support for this ‘anti-cancer’ hypothesis in the current literature. Importantly, we suggest that ectothermic taxa, with variation in somatic telomerase expression across tissue and taxa, may hold the key to understanding ongoing selection and evolution of telomerase dynamics in the wild. We further review endotherm-specific effects of growth on telomeres, effects of autotomy (‘tail dropping’) on telomere attrition, and costs of maintaining sexual displays measured in telomere attrition. Finally, we cover plant ectotherm telomeres and life histories in a separate ‘mini review’.
This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.
In this study, we have revised the rules and parameters for one of the most commonly used empirical pK a predictors, PROPKA, based on better physical description of the desolvation and dielectric ...response for the protein. We have introduced a new and consistent approach to interpolate the description between the previously distinct classifications into internal and surface residues, which otherwise is found to give rise to an erratic and discontinuous behavior. Since the goal of this study is to lay out the framework and validate the concept, it focuses on Asp and Glu residues where the protein pK a values and structures are assumed to be more reliable. The new and improved implementation is evaluated and discussed; it is found to agree better with experiment than the previous implementation (in parentheses): rmsd = 0.79 (0.91) for Asp and Glu, 0.75 (0.97) for Tyr, 0.65 (0.72) for Lys, and 1.00 (1.37) for His residues. The most significant advance, however, is in reducing the number of outliers and removing unreasonable sensitivity to small structural changes that arise from classifying residues as either internal or surface.
This review examines whether dynamical effects contribute significantly to enzyme catalysis. Computer simulations are used to address this question quantitatively.
Detection and avoidance of sick individuals have been proposed as essential components in a behavioural defence against disease, limiting the risk of contamination. However, almost no knowledge ...exists on whether humans can detect sick individuals, and if so by what cues. Here, we demonstrate that untrained people can identify sick individuals above chance level by looking at facial photos taken 2 h after injection with a bacterial stimulus inducing an immune response (2.0 ng kg−1 lipopolysaccharide) or placebo, the global sensitivity index being d′ = 0.405. Signal detection analysis (receiver operating characteristic curve area) showed an area of 0.62 (95% confidence intervals 0.60–0.63). Acutely sick people were rated by naive observers as having paler lips and skin, a more swollen face, droopier corners of the mouth, more hanging eyelids, redder eyes, and less glossy and patchy skin, as well as appearing more tired. Our findings suggest that facial cues associated with the skin, mouth and eyes can aid in the detection of acutely sick and potentially contagious people.
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