Conformational analysis and clustering of short and medium size loops connecting regular secondary structures: a database for modeling and prediction.

Loops are regions of nonrepetitive conformation connecting regular secondary structures. We identified 2,024 loops of one to eight residues in length, with acceptable main-chain bond lengths and peptide bond angles, from a database of 223 protein and protein-domain structures. Each loop is characterized by its sequence, main-chain conformation, and relative disposition of its bounding secondary structures as described by the separation between the tips of their axes and the angle between them. Loops, grouped according to their length and type of their bounding secondary structures, were superposed and clustered into 161 conformational classes, corresponding to 63% of all loops. Of these, 109 (51% of the loops) were populated by at least four nonhomologous loops or four loops sharing a low sequence identity. Another 52 classes, including 12% of the loops, were populated by at least three loops of low sequence similarity from three or fewer nonhomologous groups. Loop class suprafamilies resulting from variations in the termini of secondary structures are discussed in this article. Most previously described loop conformations were found among the classes. New classes included a 2:4 type IV hairpin, a helix-capping loop, and a loop that mediates dinucleotide-binding. The relative disposition of bounding secondary structures varies among loop classes, with some classes such as beta-hairpins being very restrictive. For each class, sequence preferences as key residues were identified; those most frequently at these conserved positions than in proteins were Gly, Asp, Pro, Phe, and Cys. Most of these residues are involved in stabilizing loop conformation, often through a positive phi conformation or secondary structure capping. Identification of helix-capping residues and beta-breakers among the highly conserved positions supported our decision to group loops according to their bounding secondary structures. Several of the identified loop classes were associated with specific functions, and all of the member loops had the same function; key residues were conserved for this purpose, as is the case for the parvalbumin-like calcium-binding loops. A significant number, but not all, of the member loops of other loop classes had the same function, as is the case for the helix-turn-helix DNA-binding loops. This article provides a systematic and coherent conformational classification of loops, covering a broad range of lengths and all four combinations of bounding secondary structure types, and supplies a useful basis for modelling of loop conformations where the bounding secondary structures are known or reliably predicted.     

Ligand recognition in μ opioid receptor: experimentally based modeling of μ opioid receptor binding sites and their testing by ligand docking

For three-dimensional understanding of the mechanisms that control potency and selectivity of the ligand binding at the atomic level, we have analysed opioid receptor-ligand interaction based on the receptor's 3D model. As a first step, we have constructed molecular models for the multiple opioid receptor subtypes using bacteriorhodopsin as a template. The S-activated dihydromorphine derivatives should serve as powerful tools in mapping the three-dimensional structure of the μ opioid receptor, including the nature of the agonist-mediated conformational change that permits G protein-coupling to ‘second messenger’ effector molecules, and in identifying specific ligand-binding contacts with the μ opioid receptor. The analyses of the interactions of some opioid ligands with the predicted ligand binding sites are consistent with the results of the affinity labeling experiments.     

Coding of odor intensity in a steady-state deterministic model of an olfactory receptor neuron

The coding of odor intensity by an olfactory receptor neuron model was studied under steady-state stimulation. Our model neuron is an elongated cylinder consisting of the following three components: a sensory dendritic region bearing odorant receptors, a passive region consisting of proximal dendrite and cell body, and an axon. First, analytical solutions are given for the three main physiological responses: (1) odorant-dependent conductance change at the sensory dendrite based on the Michaelis-Menten model, (2) generation and spreading of the receptor potential based on a new solution of the cable equation, and (3) firing frequency based on a Lapicque model. Second, the magnitudes of these responses are analyzed as a function of odorant concentration. Their dependence on chemical, electrical, and geometrical parameters is examined. The only evident gain in magnitude results from the activation-to-conductance conversion. An optimal encoder neuron is presented that suggests that increasing the length of the sensory dendrite beyond about 0.3 space constant does not increase the magnitude of the receptor potential. Third, the sensivities of the responses are examined as functions of (1) the concentration at half-maximum response, (2) the lower and upper concentrations actually discriminated, and (3) the width of the dynamic range. The overall gain in sensitivity results entirely from the conductance-to-voltage conversion. The maximum conductance at the sensory dendrite appears to be the main tuning constant of the neuron because it determines the shift toward low concentrations and the increase in dynamic range. The dynamic range of the model cannot exceed 5.7 log units, for a sensitivity increase at low odor concentration is compensated by a sensitivity decrease at high odor concentration.     

Investigations of peptide hydration using NMR and molecular dynamics simulations: A study of effects of water on the conformation and dynamics of antamanide

Summary The influence of water binding on the conformational dynamics of the cyclic decapeptide antamanide dissolved in the model lipophilic environment chloroform is investigated by NMR relaxation measurements. The water-peptide complex has a lifetime of 35 s at 250 K, which is longer than typical lifetimes of water-peptide complexes reported in aqueous solution. In addition, there is a rapid intracomplex mobility that probably involves librational motions of the bound water or water molecules hopping between different binding sites. Water binding restricts the flexibility of antamanide. The experimental findings are compared with GROMOS molecular dynamics simulations of antamanide with up to eight bound water molecules. Within the simulation time of 600 ps, no water molecule leaves the complex. Additionally, the simulations show a reduced flexibility for the complex in comparison with uncomplexed antamanide. Thus, there is a qualitative agreement between the experimental NMR results and the computer simulations.     

心肌电兴奋传导速度对心律失常影响的仿真研究

心电场是由心肌的电活动产生的。心肌细胞的电特性及心肌细胞间的传导关系决定了体表电位的分布及心电图的变化。心肌电兴奋传导速度则是影响心肌间兴奋传导关系的重要参数之一。由于很难通过实验方法来人为改变电兴奋传导速度,因而临床上有关该参数对心律影响的定量知识相当缺乏。本文采用真实三雏躯干模型及心脏模型,对心肌电兴奋传导速度与心律变化的关系进行定量仿真研究。结果表明,兴奋传导速度决定了整个心电图的变化,而局部普通心肌的传导速度在相当范围内变化似乎对心电图影响不明显,但传导速度超过一定范围后可能产生突变。     

基于结构比较的蛋白质同源模建系统及其评估Ⅱ侧链的安装

至今,有关蛋白质侧链的同源模建,除了在本体模板上安装侧链和少数限制条件下在同源模板上安装侧链的报道外,系统的研究和实施似乎还未见报道。本软件系统ＰＭＯＤＥＬＩＮＧ采用同源移植和“死端排除“相结合的侧链安装策略,对与模板蛋白相应践基具有相似大小和形状的目标残基采用直接移植的方法。其余铡链则用广义“死端排除定则”安装。经众多蛋白的测试,达到了较好的模建品质。     

Thoughts on the origin and nature of life and intelligence on earth

Believing, for good reasons, that our Universe engenders the occurrence of Life, it is probable that Life appeared more than once on young planet Earth. The universality of our genetic code indicates though, that only one line produced a population that was cellular, autopoietic, responsive intelligently (i.e., to its advantage) to its environment, and capable of reproduction. Its evolution took time during which other intermediate or incipient forms of life disappeared. Trying to retrace ab initio the preceding chemical evolution on our young planet, we may not repeat the chemistry which led to our line. One can argue that it may be profitable to attempt to construct artificial life forms using the kind of building blocks that we learned to know through studying the chemistry of our life. Independently, computers are being built, or are planned, which possess memory that can be used appropriately (intelligently), and which to some extent can repair and reproduce themselves. Such Life does not depend on our biochemistry. However, these machines do perform as yet only partly along the lines of our human intelligence which is guided by self-awareness and a sense of individual integrity, and are thereby not equipped to search for Understanding and Self-expression.     

Mathematical simulation of the interactions among cyanobacteria, purple sulfur bacteria and chemotrophic sulfur bacteria in microbial mat communities

Abstract: A deterministic one-dimensional reaction diffusion model was constructed to simulate benthic stratification patterns and population dynamics of cyanobacteria, purple and colorless sulfur bacteria as found in marine microbial mats. The model involves the major biogeochemical processes of the sulfur cycle and includes growth metabolism and their kinetic parameters as described from laboratory experimentation. Hence, the metabolic production and consumption processes are coupled to population growth. The model is used to calculate benthic oxygen, sulfide and light profiles and to infer spatial relationships and interactions among the different populations. Furthermore, the model is used to explore the effect of different abiotic and biotic environmental parameters on the community structure. A strikingly clear pattern emerged of the interaction between purple and colorless sulfur bacteria: either colorless sulfur bacteria dominate or a coexistence is found of colorless and purple sulfur bacteria. The model predicts that purple sulfur bacteria only proliferate when the studied environmental parameters surpass well-defined threshold levels. However, once the appropriate conditions do occur, the purple sulfur bacteria are extremely successful as their biomass outweighs that of colorless sulfur bacteria by a factor of up to 17. The typical stratification pattern predicted closely resembles the often described bilayer communities which comprise a layer of purple sulfur bacteria below a cyanobacterial top-layer; colorless sulfur bacteria are predicted to sandwich in between both layers. The profiles of oxygen and sulfide shift on a diel basis similarly as observed in real systems.     

Evaluation of several methods for estimating phylogenetic trees when substitution rates differ over nucleotide sites

Several maximum likelihood and distance matrix methods for estimating phylogenetic trees from homologous DNA sequences were compared when substitution rates at sites were assumed to follow a gamma distribution. Computer simulations were performed to estimate the probabilities that various tree estimation methods recover the true tree topology. The case of four species was considered, and a few combinations of parameters were examined. Attention was applied to discriminating among different sources of error in tree reconstruction, i.e., the inconsistency of the tree estimation method, the sampling error in the estimated tree due to limited sequence length, and the sampling error in the estimated probability due to the number of simulations being limited. Compared to the least squares method based on pairwise distance estimates, the joint likelihood analysis is found to be more robust when rate variation over sites is present but ignored and an assumption is thus violated. With limited data, the likelihood method has a much higher probability of recovering the true tree and is therefore more efficient than the least squares method. The concept of statistical consistency of a tree estimation method and its implications were explored, and it is suggested that, while the efficiency (or sampling error) of a tree estimation method is a very important property, statistical consistency of the method over a wide range of, if not all, parameter values is prerequisite.     

Thermal isoelectric precipitation of alpha-lactalbumin from a whey protein concentrate: Influence of protein-calcium complexation

The selective precipitation of alpha-lactalbumin (alpha-LA) at a pH around its isoelectric point (4.2) under heat treatment is the basis for a fractionation process of whey proteins. As precipitation is a phenomenon dependent on the protein hydrophobicity, and as the release of the tightly bound calcium occurring at pH around 4 modifies the alpha-LA hydrophobicity, the specific role of calcium on isoelectric precipitation is investigated. A study of the extent of alpha-LA precipitation in a whey protein concentrate under various operating conditions of pH, temperature, protein concentration, and calcium content is presented. We propose a mechanism for this phenomenon as a combination of a complexation equilibrium and of an irreversible precipitation, to account for the influence of temperature, alpha-LA concentration total ionic content, and calcium concentration, and also to estimate the complexation equilibrium constant. (c) 1995 John Wiley & Sons, Inc.