Computer Simulation of Fermentation Systems

Results of batch fermentation of gluconic acid by Pseudomonas ovalis were graphically analyzed to obtain a kinetic model to represent the data. Since gluconic acid was produced by the hydrolysis of a lactone intermediate, the model was necessarily represented by a set of kinetic equations. A computer simulation technique involving the use of the MIDAS program was developed to solve the system of nonlinear equations and to check the appropriateness of the model. Since the maximal specific growth rate and the rate constant for the production of the lactone intermediate varied with time, function generators were used to simulate these system parameters. The merit of using the MIDAS program was considered in relation to analysis and model testing in microbiological processes of similar types.     

Aqueous Hydration of Nucleic Acid Constituents: Monte Carlo Computer Simulation Studies

Abstract

Monte Carlo computer simulations were performed on dilute aqueous solutions of thymine, cytosine, uracil, adenine, guanine, the dimethyl phosphate anion in the gauche-gauche conformation and a ribose and deoxyribose derivative. The aqueous hydration of each molecule was analysed in terms of quasi-component distribution functions based on the Proximity Criterion, and partitioned into hydrophobic, hydrophilic and ionic contributions. Color stereo views of selected hydration complexes are also presented. A preliminary discussion of the transferability of functional group coordination numbers is given. The results enable to comment on two current problems related to the hydration of nucleic acids: a) the theory of Dickerson and coworkers on the role of water in the relative stability of the A and B forms of DNA and b) the idea of water bridges and filaments emerging from the computer simulation results on the hydration of DNA fragments by Clementi.     

Stochastic Simulation of Biomolecular Networks in Dynamic Environments

Simulation of biomolecular networks is now indispensable for studying biological systems, from small reaction networks to large ensembles of cells. Here we present a novel approach for stochastic simulation of networks embedded in the dynamic environment of the cell and its surroundings. We thus sample trajectories of the stochastic process described by the chemical master equation with time-varying propensities. A comparative analysis shows that existing approaches can either fail dramatically, or else can impose impractical computational burdens due to numerical integration of reaction propensities, especially when cell ensembles are studied. Here we introduce the Extrande method which, given a simulated time course of dynamic network inputs, provides a conditionally exact and several orders-of-magnitude faster simulation solution. The new approach makes it feasible to demonstrate—using decision-making by a large population of quorum sensing bacteria—that robustness to fluctuations from upstream signaling places strong constraints on the design of networks determining cell fate. Our approach has the potential to significantly advance both understanding of molecular systems biology and design of synthetic circuits.     

Computer Simulation by Molecular Dynamics as a Tool for Modelling of Molecular Systems

Abstract

A survey is given of methods for simulation of molecular systems on a computer. The various assumptions, approximations and limitations are discussed and the possibility of making comparisons with experimental quantities is assessed. Finally, a number of practical applications of molecular dynamics simulation techniques in chemistry are reviewed.     

Acceleration of cryo-EM Flexible Fitting for Large Biomolecular Systems by Efficient Space Partitioning

1. Download high-res image (287KB)
2. Download full-size image

     

Computer Simulation of Macromolecules

Computer simulation techniques are now an essential part of modern structural molecular biology. They are used in many different ways in order to study the conformation, dynamics and interactions of proteins and nucleic acids. In this paper, I shall review several of these applications and then focus on three specific areas, namely the conformation and dynamics of proteins including the use of free energy perturbation methods to study mutant proteins, the conformation and dynamics of DNA and DNA-drug complexes, and the use of computers with parallel architectures. Although simulation of molecules as large and complex as proteins and nucleic acids may be considered a grand challenge in itself, there are even greater challenges for the future.     

Biomolecular Engineering

Cover illustration: Biotechnology Journal's latest Special Issue on “Biomolecular Engineering” is based peer-reviewed papers derived from some of the best presentations at the 4^th International Conference on Biomolecular Engineering. The cover is a snapshot of solvated HER4/ErbB4 kinase domain with juxtamembrane region; image provided by Ravi Radhakrishnan.     

Biodegradation of N-Nitrosodimethylamine in Aqueous and Soil Systems

N-Nitrosodimethylamine (NDMA) was mineralized by microorganisms in aqueous and soil systems. Initial rates of mineralization (micrograms per milliliter per day) were calculated for a wide range of initial concentrations of NDMA (micrograms per milliliter to picograms per milliliter). Log-log plots of the data were fitted with both linear and nonlinear least-squares analyses; however, linear models provided better fits for the kinetic data in all cases. The slopes of the linear fits were not significantly different than 1.0 (P < 0.05); thus, first-order reaction kinetics were in effect over the range of concentrations tested, and saturation kinetics were not achieved. Rate constants (day⁻¹) and total percent mineralized increased with decreasing initial concentrations of NDMA. Rates of mineralization were reduced in aqueous systems when supplemental carbon was available, whereas in soils, percentages of organic matter and supplemental carbon had little effect on rates of mineralization. Implications of these results for predictions of rates and threshold limits of mineralization activity in natural systems are discussed. A laboratory scale simulated trickling filter containing an activated charcoal bed provided a suitable environment for mineralization of NDMA at concentrations of 50 and 100 μg/ml on a continuous basis. NDMA was not toxic to natural populations of microorganisms at concentrations up to 10 mg/ml. Using high-pressure liquid chromatography coupled with radioactivity detection, we identified formaldehyde and methylamine as intermediates produced during the biodegradation of NDMA.     

生物分子自组装

分子自组装是一种普遍存在于生命体系中的现象,是生命科学最本质的内容之一。开展分子自组装的研究具有重要意义,有助于人们从分子水平上认识自然界中生命形成和演变的过程,并为人们提供新的思路,开展生物医学基础研究、新材料合成及分子器件研制等。该文介绍了自组装的基本含义,对分子自组装技术在生物材料、生物分子器件研究方面的进展作了综述。     

Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model

Biomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived conformational states that are difficult to detect experimentally. For this reason, computational methods are needed to produce plausible hypothetical transition pathways that can then be probed experimentally. Here we propose a simple and computationally efficient method, called ANMPathway, for constructing a physically reasonable pathway between two endpoints of a conformational transition. We adopt a coarse-grained representation of the protein and construct a two-state potential by combining two elastic network models (ENMs) representative of the experimental structures resolved for the endpoints. The two-state potential has a cusp hypersurface in the configuration space where the energies from both the ENMs are equal. We first search for the minimum energy structure on the cusp hypersurface and then treat it as the transition state. The continuous pathway is subsequently constructed by following the steepest descent energy minimization trajectories starting from the transition state on each side of the cusp hypersurface. Application to several systems of broad biological interest such as adenylate kinase, ATP-driven calcium pump SERCA, leucine transporter and glutamate transporter shows that ANMPathway yields results in good agreement with those from other similar methods and with data obtained from all-atom molecular dynamics simulations, in support of the utility of this simple and efficient approach. Notably the method provides experimentally testable predictions, including the formation of non-native contacts during the transition which we were able to detect in two of the systems we studied. An open-access web server has been created to deliver ANMPathway results.     

Computer Simulation of Surface Segregation

Abstract

Computer simulation techniques can now reliably model the surface structure and energies of inorganic solids. We present recent work which has been directed at modelling the segregation of impurities. The techniques are based on energy minimisation where the forces between the atoms are described by the Born model of solids. We initially show that magnesium and calcium segregation to the prism surfaces of alumina reproduce the available experimental data within the uncertainties of the experimental technique. However, reliable experimental data is not always available, and hence we show using the examples of calcium segregation to zirconia surfaces can give insights to the surface structure and provide predictions for experiment to test. Secondly, the simulations can be verified by comparison with morphologies. This is illustrated by comparison of the experimentally determined morphology of calcite with magnesium and lithium impurities with those calculated. Next extensions to the energy minimisation methods are described using dynamical techniques based on lattice and molecular dynamics. Finally, we describe the situation where there is phase separation and the structure and stability of the interface is governed by the epitaxial relations between the underlying oxide and the impurity oxide.     

Computer Simulation of Orb-Web Construction

SYNOPSIS. Uloborus diversus adjusts its behavior while layingsticky spiral in response to stimuli it receives as it moves.The course of the last loop of sticky spiral determines thepath the spider takes. The spiders probably sense the anglesthe sticky spiral makes with the radius and with the last loopof spiral, and use them in making decisions to turn back.Computer-simulationhas shown that a simple turnback program using just these anglescan produce a spider-like pattern of sticky spiral.     

Virucidal Effect of Transient Electric Arcs in Aqueous Systems

Bacterial and animal viruses were inactivated by high voltage electrical discharges in water. The sensitivity of phages to the immediate component of this effect was correlated to the sensitivity to ultraviolet radiation. Transient electrical arcs in weak electrolytes also generated chemical compounds which were virucidal against phages T3, T5, and varphiX174 but were only slightly virucidal against phages T2 and T4.     

Biomolecular diffusional association

The primary method for the computational study of biomolecular diffusional association is Brownian dynamics. Recent work has seen advances in the efficiency of computing association rates and in the accuracy of simulation models. New areas to which Brownian dynamics has been applied include protein polymerisation and protein adsorption to a surface. There has recently been particularly intense study of protein-protein association, and Brownian dynamics, together with other theoretical and experimental approaches, has led to new insights into the determinants of protein-protein binding kinetics.