Protein flexibility and intrinsic disorder

Comparisons were made among four categories of protein flexibility: (1) low-B-factor ordered regions, (2) high-B-factor ordered regions, (3) short disordered regions, and (4) long disordered regions. Amino acid compositions of the four categories were found to be significantly different from each other, with high-B-factor ordered and short disordered regions being the most similar pair. The high-B-factor (flexible) ordered regions are characterized by a higher average flexibility index, higher average hydrophilicity, higher average absolute net charge, and higher total charge than disordered regions. The low-B-factor regions are significantly enriched in hydrophobic residues and depleted in the total number of charged residues compared to the other three categories. We examined the predictability of the high-B-factor regions and developed a predictor that discriminates between regions of low and high B-factors. This predictor achieved an accuracy of 70% and a correlation of 0.43 with experimental data, outperforming the 64% accuracy and 0.32 correlation of predictors based solely on flexibility indices. To further clarify the differences between short disordered regions and ordered regions, a predictor of short disordered regions was developed. Its relatively high accuracy of 81% indicates considerable differences between ordered and disordered regions. The distinctive amino acid biases of high-B-factor ordered regions, short disordered regions, and long disordered regions indicate that the sequence determinants for these flexibility categories differ from one another, whereas the significantly-greater-than-chance predictability of these categories from sequence suggest that flexible ordered regions, short disorder, and long disorder are, to a significant degree, encoded at the primary structure level.     

Divided genomes and intrinsic noise

Summary Segmental genomes (i.e., genomes in which the genetic information is dispersed between two or more discrete molecules) are abundant in RNA viruses, but virtually absent in DNA viruses. It has been suggested that the division of information in RNA viruses expands the pool of variation available to natural selection by providing for the reassortment of modular RNAs from different genetic sources. This explanation is based on the apparent inability of related RNA molecules to undergo the kinds of physical recombination that generate variation among related DNA molecules. In this paper we propose a radically different hypothesis. Self-replicating RNA genomes have an error rate of about 10^–3–10^–4 substitutions per base per generation, whereas for DNA genomes the corresponding figure is 10^–9–10^–11. Thus the level of noise in the RNA copier process is five to eight orders of magnitude higher than that in the DNA process. Since a small module of information has a higher chance of passing undamaged through a noisy channel than does a large one, the division of RNA viral information among separate small units increases its overall chances of survival. The selective advantage of genome segmentation is most easily modelled for modular RNAs wrapped up in separate viral coats. If modular RNAs are brought together in a common viral coat, segmentation is advantageous only when interactions among the modular RNAs are selective enought to provide some degree of discrimination against miscopied sequences. This requirement is most clearly met by the reoviruses.     

On conditional and intrinsic autoregressions

Gaussian conditional autoregressions have been widely used inspatial statistics and Bayesian image analysis, where they areintended to describe interactions between random variables atfixed sites in Euclidean space. The main appeal of these distributionsis in the Markovian interpretation of their full conditionals.Intrinsic autoregressions are limiting forms that retain theMarkov property. Despite being improper, they can have advantagesover the standard autoregressions, both conceptually and inpractice. For example, they often avoid difficulties in parameterestimation, without apparent loss, or exhibit appealing invariances,as in texture analysis. However, on small arrays and in nonlatticeapplications, both forms of autoregression can lead to undesirablesecond-order characteristics, either in the variables themselvesor in contrasts among them. This paper discusses standard andintrinsic autoregressions and describes how the problems thatarise can be alleviated using Dempster's (1972) algorithm oran appropriate modification. The approach represents a partialsynthesis of standard geostatistical and Gaussian Markov randomfield formulations. Some nonspatial applications are also mentioned.     

Mother's milk and intrinsic immunity

To limit the spread of retroviruses, mammals appear to have tailored a way to inhibit host-to-host infection by?milk-borne retroviruses. In this issue of Cell Host & Microbe, Okeoma et?al. (2010) reveal that the host restriction factor APOBEC3 expressed in mammary endothelial cells inactivates retroviruses released in maternal milk.     

Sensory and intrinsic coordination of movement

A recently generalized theory of perceptual guidance (general tau theory) was used to analyse coordination in skilled movement. The theory posits that (i) guiding movement entails controlling closure of spatial and/or force gaps between effectors and goals, by sensing and regulating the tau s of the gaps (the time-to-closure at current closure rate), (ii) a principal way of coordinating movements is keeping the tau s of different gaps in constant ratio (known as tau-coupling), and (iii) intrinsically paced movements are guided and coordinated by tau-coupling onto a tau-guide, tau g, generated in the nervous system and described by the equation tau g = 0.5 (t-T 2/t) where T is the duration of the body movement and t is the time from the start of the movement. Kinematic analysis of hand to mouth movements by human adults, with eyes open or closed, indicated that hand guidance was achieved by maintaining, during 80 85% of the movement, the tau-couplings tau alpha-tau r and tau r-tau g, where tau r is tau of the hand-mouth gap, tau alpha is tau of the angular gap to be closed by steering the hand and tau g is an intrinsic tau-guide.     

NMR illuminates intrinsic disorder

Nuclear magnetic resonance (NMR) has long been instrumental in the characterization of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). This method continues to offer rich insights into the nature of IDPs in solution, especially in combination with other biophysical methods such as small-angle scattering, single-molecule fluorescence, electron paramagnetic resonance (EPR), and mass spectrometry. Substantial advances have been made in recent years in studies of proteins containing both ordered and disordered domains and in the characterization of problematic sequences containing repeated tracts of a single or a few amino acids. These sequences are relevant to disease states such as Alzheimer's, Parkinson's, and Huntington's diseases, where disordered proteins misfold into harmful amyloid. Innovative applications of NMR are providing novel insights into mechanisms of protein aggregation and the complexity of IDP interactions with their targets. As a basis for understanding the solution structural ensembles, dynamic behavior, and functional mechanisms of IDPs and IDRs, NMR continues to prove invaluable.     

Ecosystem functioning and intrinsic value of biodiversity

Trying to show the importance of biodiversity for ecosystem functioning, ecologists are repeatedly looking for a possible connection between species diversity and intensity of various ecosystem processes. However it appears that simple "proof" of such a connection cannot easily be demonstrated and involves a lot of contingencies. The different meanings of "ecosystem functioning" may be crucial for attempts to show the importance of biodiversity and to assess possible redundancy. If "ecosystem functioning" means only total production of organic matter or consumption of CO₂ then some degree of redundancy in species diversity of autotrophs will be obvious in most cases. However if "ecosystem functioning" includes the synthesis of all compounds that plants, animals and other organisms of a given community contain in their bodies or release in the environment, then any decrease in species diversity will be meaningful and any redundancy will be impossible by definition. In accordance with such a definition biodiversity obviously cannot be diminished without some loss of ecosystem functioning. I emphasize that attempts to conserve biodiversity do not need special justification in possible relationships between diversity and ecosystem services. If biodiversity has intrinsic value it means that it could in principle be "useless" for human needs or for "ecosystem functioning".     

Detergents as intrinsic P-glycoprotein substrates and inhibitors

We assessed the interaction of three electrically neutral detergents (Triton X-100, C₁₂EO₈, and Tween 80) with P-glycoprotein (ABCB1, MDR1) and identified the molecular elements responsible for this interaction. To this purpose we titrated P-glycoprotein in inside-out plasma membrane vesicles of MDR1-transfected mouse embryo fibroblasts (NIH-MDR1-G185) with the detergents below their critical micelle concentration, CMC. The P-glycoprotein ATPase measured as a function of the detergent concentration yielded bell-shaped activity curves which were evaluated with a two-site binding model. The lipid-water partition coefficient and the transporter-water binding constant of the detergents were measured independently. Knowledge of these two parameters allowed assessment of the free energy of detergent binding to P-glycoprotein in the lipid membrane, ΔG_tl⁰, that reflects the direct detergent-transporter affinity. It increased as the number of ethoxyl groups increased, suggesting that these hydrogen bond acceptor groups are the key elements for the detergent-transporter interaction in the lipid membrane. The free energy of binding to P-glycoprotein per ethoxyl group (EO) was determined as approximately ΔG_EO⁰ = − 1.6 kJ/mol. The present findings moreover document that, depending on the concentration applied, detergents are intrinsic substrates for, or inhibitors of P-glycoprotein.     

Structured proteins and proteins with intrinsic disorder

Until recently, the point of view that the unique tertiary structure is necessary for protein function has prevailed. However, recent data have demonstrated that many cell proteins do not possess such structure in isolation, although displaying a distinct function under physiological conditions. These proteins were named the naturally, or intrinsically, disordered proteins. The fraction of intrinsically disordered regions in such proteins may vary from several amino acid residues to a completely unordered sequence of several tens or even several hundreds of residues. The main distinction of these proteins from structured (globular) proteins is that they have no unique tertiary structure in isolation and acquire it only upon interaction with their partners. The conformation of these proteins in a complex is determined not only by their own amino acid sequence (as is typical of structured, or globular, proteins) but also by the interacting partner. This review discusses the structure-function relationships in structured and intrinsically disordered proteins. The intricateness of this problem and the possible ways to solve it are illustrated by the example of the EF1A elongation factor family.     

Hydrational and intrinsic compressibilities of globular proteins

Partial compressibilities of globular proteins in water are reviewed. Contribution of hydrational and of intrinsic compressibilities to experimental partial quantity have been evaluated from ultrasonic data using two independent methods: (a) additive calculation of the hydrational contributions of the surface atomic groups and (b) an analysis of correlation between partial compressibility and molecular surface area. The value (14 ± 3) × 10^?6 bar ^?1 for the isothermal compressibility coefficient of the protein interior at 25°C was obtained as an average value for variety of globular proteins. This value is similar to that of solid organic polymers. Possible relaxation contribution to partial compressibility is roughly estimated from comparison of thermodynamic with x-ray data on protein compressibility. The average compressibility of water in the hydration shell of proteins was found to be 35 × 10^?6 bar ^?1, which is 20% less than that of pure water. © 1993 John Wiley & Sons, Inc.     

Capturing intrinsic nanomechanics of allostery

The Hsp70 chaperone exploits allosteric communication between its substrate binding domain and its nucleotide binding domain to regulate the loading and release of misfolded polypeptides in an ATP-hydrolysis-dependent manner. In this issue of Biophysical Journal, Singh, Rief, and ?oldák report an exquisitely detailed study of the nanomechanical aspects of the allosteric mechanism in DnaK, an Escherichia coli heat shock protein 70 chaperone.