Computer simulated modeling of biomolecular systems.

This paper describes the algorithm of a program used to simulate three dimensional models of molecules. In addition to open ended molecules the program also enables simulation of structures with constraints in the form of cyclic regions or fixed location of particular atoms. Several molecules can be handled in a single run and each molecule can have any number of contraints. Further, any number of conformations can be obtained for each constrained region. The program can be used for research in several areas of molecular biology, e.g., structure determination, conformational analysis and topographic comparisons.     

Optimization of a stochastically simulated gene network model via simulated annealing

By rearranging naturally occurring genetic components, gene networks can be created that display novel functions. When designing these networks, the kinetic parameters describing DNA/protein binding are of great importance, as these parameters strongly influence the behavior of the resulting gene network. This article presents an optimization method based on simulated annealing to locate combinations of kinetic parameters that produce a desired behavior in a genetic network. Since gene expression is an inherently stochastic process, the simulation component of simulated annealing optimization is conducted using an accurate multiscale simulation algorithm to calculate an ensemble of network trajectories at each iteration of the simulated annealing algorithm. Using the three-gene repressilator of Elowitz and Leibler as an example, we show that gene network optimizations can be conducted using a mechanistically realistic model integrated stochastically. The repressilator is optimized to give oscillations of an arbitrary specified period. These optimized designs may then provide a starting-point for the selection of genetic components needed to realize an in vivo system.     

Computer simulation on the cooperation of functional molecules during the early stages of evolution

It is very likely that life began with some RNA (or RNA-like) molecules, self-replicating by base-pairing and exhibiting enzyme-like functions that favored the self-replication. Different functional molecules may have emerged by favoring their own self-replication at different aspects. Then, a direct route towards complexity/efficiency may have been through the coexistence/cooperation of these molecules. However, the likelihood of this route remains quite unclear, especially because the molecules would be competing for limited common resources. By computer simulation using a Monte-Carlo model (with "micro-resolution" at the level of nucleotides and membrane components), we show that the coexistence/cooperation of these molecules can occur naturally, both in a naked form and in a protocell form. The results of the computer simulation also lead to quite a few deductions concerning the environment and history in the scenario. First, a naked stage (with functional molecules catalyzing template-replication and metabolism) may have occurred early in evolution but required high concentration and limited dispersal of the system (e.g., on some mineral surface); the emergence of protocells enabled a "habitat-shift" into bulk water. Second, the protocell stage started with a substage of "pseudo-protocells", with functional molecules catalyzing template-replication and metabolism, but still missing the function involved in the synthesis of membrane components, the emergence of which would lead to a subsequent "true-protocell" substage. Third, the initial unstable membrane, composed of prebiotically available fatty acids, should have been superseded quite early by a more stable membrane (e.g., composed of phospholipids, like modern cells). Additionally, the membrane-takeover probably occurred at the transition of the two substages of the protocells. The scenario described in the present study should correspond to an episode in early evolution, after the emergence of single "genes", but before the appearance of a "chromosome" with linked genes.     

Determinants of simulated RNA evolution

Models of RNA secondary structure folding are widely used to study evolution in theory and simulation. However, systematic studies of the parameters involved are rare. In this paper, we study by simulation how RNA evolution is influenced by three different factors, namely the mutation rate, scaling of the fitness function, and distance measure. We found that for low mutation rates the qualitative evolutionary behavior is robust with respect to the scaling of the fitness function. For efficient mutation rates, which are close to the error threshold, scaling and distance measure have a strong influence on the evolutionary behavior. A global distance measure that takes sequence information additively into account lowers the error threshold. When using a local sequence-structure alignment for the distance, we observed a smoother evolution of the fitness over time. Finally, in addition to the well known error threshold, we identify another threshold of the mutation rate, called divergence threshold, where the qualitative transient behavior changes from a localized to an exploratory search.     

Computer simulation of a model network for the erythrocyte cytoskeleton.

The geometry and mechanical properties of the human erythrocyte membrane cytoskeleton are investigated by a computer simulation in which the cytoskeleton is represented by a network of polymer chains. Four elastic moduli as well as the area and thickness are predicted for the chain network as a function of temperature and the number of segments in each chain. Comparisons are made with mean field arguments to examine the importance of steric interactions in determining network properties. Applied to the red blood cell, the simulation predicts that in the bilayer plane the membrane cytoskeleton has a shear modulus of 10 +/- 2 x 10(-6) J/m2 and an areal compression modulus of 17 +/- 2 x 10(-6) J/m2. The volume compression modulus and the transverse Young's modulus of the cytoskeleton are predicted to be 1.2 +/- 0.1 x 10(3) J/m3 and 2.0 +/- 0.1 x 10(3) J/m3, respectively. Elements of the cytoskeleton are predicted to have a mean displacement from the bilayer plane of 15 nm. The simulation agrees with some, but not all, of the shear modulus measurements. The other predicted moduli have not been measured.     

Computer simulations of mass transport for nonidentical interacting molecules.

We have developed a system for simulating the mass transport properties of interacting nonidentical macromolecules where the association is of the form A + B ? C, C + B ? D. Our simulation programs operate in a minicomputer (PDP 1104) with 16K of core and provide results identical to methods previously usable only with large computers. We use a rectangular approximation for the centrifuge cell which greatly simplifies calculation, although it introduces a few percent error into any attempt at quantitative fitting of actual data. The program as written is directly applicable to gel chromatography, simply by substitution of flow for centrifugal field and dispersion for diffusion. Simulations of centrifuge results have been compared with experimental results for two systems which have been proposed to fit the association pattern described—nitrogenase components and an antigen-antibody interaction. In both cases the results of our simulations suggest that the accepted interpretation of the experimental results may need to be modified. For the antigen-antibody interaction, the presence of multivalent higher order complexes apparently is required to explain the centrifuge results. For nitrogenase, one cannot readily distinguish the case of association to form both 1:1 and 1:2 molar complexes from that of formation of only the 1:1 complex on the basis of the published data. Criteria for making such a discrimination are discussed.     

Computer design of bioactive molecules: a method for receptor-based de novo ligand design.

The design of molecules to bind specifically to protein receptors has long been a goal of computer-assisted molecular design. Given detailed structural knowledge of the target receptor, it should be possible to construct a model of a potential ligand, by algorithmic connection of small molecular fragments, that will exhibit the desired structural and electrostatic complementarity with the receptor. However, progress in this area of receptor-based, de novo ligand design has been hampered by the complexity of the construction process, in which potentially huge numbers of structures must be considered. By limiting the scope of the structure-space examined to one particular class of ligands--namely, peptides and peptide-like compounds--the problem complexity has been reduced to the point that successful, de novo design is now possible. The methodology presented employs a large template set of amino acid conformations which are iteratively pieced together in a model of the target receptor. Each stage of ligand growth is evaluated according to a molecular mechanics-based energy function, which considers van der Waals and coulombic interactions, internal strain energy of the lengthening ligand, and desolvation of both ligand and receptor. The search space is managed by use of a data tree which is kept under control by pruning according to the energy evaluation. Ligands grown by this procedure are subjected to follow-up evaluation in which an approximate binding enthalpy is determined. This methodology has proven useful as a precise model-builder and has also shown the ability to design bioactive ligands.     

Protein evolution on a human signaling network

Background  

The architectural structure of cellular networks provides a framework for innovations as well as constraints for protein evolution. This issue has previously been studied extensively by analyzing protein interaction networks. However, it is unclear how signaling networks influence and constrain protein evolution and conversely, how protein evolution modifies and shapes the functional consequences of signaling networks. In this study, we constructed a human signaling network containing more than 1,600 nodes and 5,000 links through manual curation of signaling pathways, and analyzed the d _N/d _S values of human-mouse orthologues on the network.     

Dissociating quaternary structure regulates cell-signaling functions of a secreted human tRNA synthetase

Many tRNA synthetases are homodimers that are catalytically inactive as monomers. An example is the 528-amino acid human tyrosyl-tRNA synthetase, which is made up of an N-terminal catalytic unit (TyrRS(Mini)) and a 164-amino acid C-domain. Although native TyrRS has no known cytokine functions, natural proteolysis of secreted TyrRS releases TyrRS(Mini), which not only has the same aminoacylation activity as native TyrRS but also has strong activity for stimulating migration of polymorphonuclear leukocytes. The migration-stimulating activity is dependent on an ELR tripeptide motif, similar to that in CXC cytokines like IL-8, and also has the familiar bell-shaped concentration dependence seen for CXC cytokines. Here we show that in contrast to IL-8, where the bell-shaped dependence arises from the effects of CXCR1/2 receptor internalization, TyrRS(Mini) does not induce internalization of CXCR1/2. A rationally designed non-associating monomer and a non-dissociating dimer were constructed. With these constructs, the bell-shaped concentration dependence of leukocyte migration was shown to arise from the agonist (for migration) activity of the catalytically inactive monomer and the antagonist activity of the catalytically active dimer. Thus, the dissociating quaternary structure of TyrRS(Mini) regulates two opposing cytokine activities and suggests the possibility of dissociating quaternary structures regulating novel functions of other tRNA synthetases.     

Computer simulated host selection in Ips typographus

Foraging behaviour by Ips typographus L. (Coleoptera; Scolytidae) was simulated to assess host finding and reproductive success of beetles following four different strategies: 1. random search, 2. upwind search, in which beetles follow a prevailing flight direction, 3. random search with short range olfactory attraction to susceptible trees (primary attraction), and 4. upwind search with primary attraction. For each strategy we varied three parameters in equidistant steps including number of susceptible trees per hectare (0.06–0.33), population size (200–1000 beetles), and flight capacity (500–3000 m). All possible combinations of these parameters were tested in 12 replicates with more than 400 000 imaginary beetles flown through the simulated forest. Reproductive success of strategy 4, which combined upwind flight with primary attraction, exceeded that of the other strategies (1–3) circa 27, 7, and 4 times, respectively. In random search, maintenance of the population required a flight capacity, population size and host tree abundance which are unlikely to occur at suboutbreak levels in nature.

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Zusammenfassung Die Wirtsbaumsuche des Buchdruckers wurde in einem Computermodell simuliert und Wirtsbaumfindung und Fortpflanzungserfolg in 4 verschiedenen Suchstrategien quantifiziert: 1. Zufallssuche, 2. Gegenwindsuche, in der die Käfer einer Hauptflugrichtung folgen, 3. Zufallssuche mit Wahrnehmung des bruttauglichen Wirtsbaumes aus kurzer Distanz (primäre Attraktivität), und 4. Gegenwindsuche mit primärer Attraktivität. Für jede Strategie wurden 3 Parameter in äquidistanten Schritten verändert: die Anzahl bruttauglicher Bäume pro Hektar (0.06–0.33), die Populationsdichte der Käfer (200–1000) und die Flugkapazität der Käfer (500–3000 m). Alle möglichen Kombinationen dieser Parameter wurden in 12 Wiederholungen getestet und daher mehr als 400 000 imaginäre Käfer durch den Modellwald geflogen. Der Fortpflanzungserfolg in Strategie 4, die Gegenwindsuche mit Wahrnehmung des Wirtsbaumes aus kurzer Distanz kombinierte, übertraf den in Strategie 1, 2 und 3 circa 27-, 7-, bzw 4-fach. Zur Erhaltung der Käferpopulation waren in der Zufallssuche eine Populationsdichte, Flugkapazität und Wirtsbaumdichte erforderlich, wie sie in der endemischen Phase wohl kaum anzutreffen sind.

     

Computer simulation of inhibition-dependent binding in a neural network

Reverberating dynamics of neural network is modeled on PC in order to illustrate possible role of inhibition as binding controller in the network. The network is composed of binding neurons. In the binding neuron model [BioSystems 48 (1998) 263], the degree of temporal coherence between synaptic inputs is decisive for triggering, and slow inhibition is expressed in terms of the degree, which is necessary for triggering. Two learning mechanisms are implemented in the network, namely, adjusting synaptic strength and/or propagation delays. By means of forced playing of external pattern, the network is taught to support dynamics with disconnected and bound patterns of activity. By choosing either high, or low inhibition, one can switch between the disconnected and bound patterns, respectively. This is interpreted as inhibition-controlled binding in the network.     

Bringing molecules back into molecular evolution

Much molecular-evolution research is concerned with sequence analysis. Yet these sequences represent real, three-dimensional molecules with complex structure and function. Here I highlight a growing trend in the field to incorporate molecular structure and function into computational molecular-evolution work. I consider three focus areas: reconstruction and analysis of past evolutionary events, such as phylogenetic inference or methods to infer selection pressures; development of toy models and simulations to identify fundamental principles of molecular evolution; and atom-level, highly realistic computational modeling of molecular structure and function aimed at making predictions about possible future evolutionary events.     

Role of interstellar molecules in prebiological evolution

Three generations of organic molecules in space are considered: interstellar molecules, molecules synthesised in protosolar cloud and molecules synthesised on the Earth. It is shown that there is no possibilities for amino acid polymers to be synthesised under interstellar cloud conditions. Molecules of the second generation were disintegrated during the Earth accumulation period. The problem of the origin of life is connected with the evolution of molecules of the third generation.     

Interactions of molecules with nucleic acids. VI. Computer design of chromophoric intercalating agents

The mode of action of many antitumor agents entails the inhibition of nucleic acid synthesis. Because many of the drugs can intercalate, it is assumed that intercalation is an important step in the mechanism of biological activity. As intercalants contain a planar chromophore as an ingredient essential for intercalation, chromophores that should fit into DNA are desired. This is the main theme of this investigation. Binding to DNA of fundamental moieties, protonated pyridine, aniline, phenol, quinone, and 4H-thiopyran-4-one, is studied to determine their optimum placement in DNA. The optimum orientations for each moiety are superimposed to form polyaromatic systems that can intercalate in a manner in which functional groups on these chromophores are oriented as in the moieties themselves. Ideal intercalants proposed contain three and four fused ring system, have protonated ring nitrogen atoms located to maximize the electrostatic interactions with DNA, hydroxy and amino groups that can hydrogen bond to the O_II and O_5′ phosphate backbone atoms, and carbonyl and sulfur groups in the central position of the ring system to provide variations in the chromophore and to interact with the relatively positive region in the intercalation site. The optimum orientation occurs when the chromophore and the base pairs overlap to the maximum extent. The ideal intercalants are fundamentally of the type:      

Chemical evolution,recent syntheses of bioorganic molecules

This review covers important developments in abiological synthesis of biomonomers and biopolymers since about 1967. The significance of these experiments to the field of chemical evolution and the origin of life is also discussed. Lunar Science Institute Contribution. Continuation of: Oró, J.: ‘Extraterrestrial Organic Analysis’,Space Life Sci. 3 (1972), 507.