Molecular dynamics simulations with coarse-grained and/or simplified Hamiltonians are an effective means of capturing the functionally important long-time and large-length scale motions of proteins and RNAs. Structure-based Hamiltonians, simplified models developed from the energy landscape theory of protein folding, have become a standard tool for investigating biomolecular dynamics. SMOG@ctbp is an effort to simplify the use of structure-based models. The purpose of the web server is two fold. First, the web tool simplifies the process of implementing a well-characterized structure-based model on a state-of-the-art, open source, molecular dynamics package, GROMACS. Second, the tutorial-like format helps speed the learning curve of those unfamiliar with molecular dynamics. A web tool user is able to upload any multi-chain biomolecular system consisting of standard RNA, DNA and amino acids in PDB format and receive as output all files necessary to implement the model in GROMACS. Both Cα and all-atom versions of the model are available. SMOG@ctbp resides at http://smog.ucsd.edu.
We introduce the software package ReaDDy for simulation of detailed spatiotemporal mechanisms of dynamical processes in the cell, based on reaction-diffusion dynamics with particle resolution. In contrast to other particle-based reaction kinetics programs, ReaDDy supports particle interaction potentials. This permits effects such as space exclusion, molecular crowding and aggregation to be modeled. The biomolecules simulated can be represented as a sphere, or as a more complex geometry such as a domain structure or polymer chain. ReaDDy bridges the gap between small-scale but highly detailed molecular dynamics or Brownian dynamics simulations and large-scale but little-detailed reaction kinetics simulations. ReaDDy has a modular design that enables the exchange of the computing core by efficient platform-specific implementations or dynamical models that are different from Brownian dynamics.
To facilitate analysis and understanding of biological systems, large-scale data are often integrated into models using a variety of mathematical and computational approaches. Such models describe the dynamics of the biological system and can be used to study the changes in the state of the system over time. For many model classes, such as discrete or continuous dynamical systems, there exist appropriate frameworks and tools for analyzing system dynamics. However, the heterogeneous information that encodes and bridges molecular and cellular dynamics, inherent to fine-grained molecular simulation models, presents significant challenges to the study of system dynamics. In this paper, we present an algorithmic information theory based approach for the analysis and interpretation of the dynamics of such executable models of biological systems. We apply a normalized compression distance (NCD) analysis to the state representations of a model that simulates the immune decision making and immune cell behavior. We show that this analysis successfully captures the essential information in the dynamics of the system, which results from a variety of events including proliferation, differentiation, or perturbations such as gene knock-outs. We demonstrate that this approach can be used for the analysis of executable models, regardless of the modeling framework, and for making experimentally quantifiable predictions.
We present a simple computational model of the dentate gyrus to evaluate the hypothesis that pattern separation, defined as the ability to transform a set of similar input patterns into a less-similar set of output patterns, is dynamically regulated by hilar neurons. Prior models of the dentate gyrus have generally fallen into two categories: simplified models that have focused on a single granule cell layer and its ability to perform pattern separation, and large-scale and biophysically realistic models of dentate gyrus, which include hilar cells, but which have not specifically addressed pattern separation. The present model begins to bridge this gap. The model includes two of the major subtypes of hilar cells: excitatory hilar mossy cells and inhibitory hilar interneurons that receive input from and project to the perforant path terminal zone (HIPP cells). In the model, mossy cells and HIPP cells provide a mechanism for dynamic regulation of pattern separation, allowing the system to upregulate and downregulate pattern separation in response to environmental and task demands. Specifically, pattern separation in the model can be strongly decreased by decreasing mossy cell function and/or by increasing HIPP cell function; pattern separation can be increased by the opposite manipulations. We propose that hilar cells may similarly mediate dynamic regulation of pattern separation in the dentate gyrus in vivo, not only because of their connectivity within the dentate gyrus, but also because of their modulation by brainstem inputs and by the axons that “backproject” from area CA3 pyramidal cells.
hippocampus; dentate gyrus; computational model; hilus; pattern separation
Human physiological functions are regulated across many orders of magnitude in space and time. Integrating the information and dynamics from one scale to another is critical for the understanding of human physiology and the treatment of diseases. Multi-scale modeling, as a computational approach, has been widely adopted by researchers in computational and systems biology. A key unsolved issue is how to represent appropriately the dynamical behaviors of a high-dimensional model of a lower scale by a low-dimensional model of a higher scale, so that it can be used to investigate complex dynamical behaviors at even higher scales of integration. In the article, we first review the widely-used different modeling methodologies and their applications at different scales. We then discuss the gaps between different modeling methodologies and between scales, and discuss potential methods for bridging the gaps between scales.
Understanding how glycosylation affects protein structure, dynamics, and function is an emerging and challenging problem in biology. As a first step toward glycan modeling in the context of structural glycobiology, we have developed Glycan Reader and integrated it into the CHARMM-GUI, http://www.charmm-gui.org/input/glycan. Glycan Reader greatly simplifies the reading of PDB structure files containing glycans through (i) detection of carbohydrate molecules, (ii) automatic annotation of carbohydrates based on their three-dimensional structures, (iii) recognition of glycosidic linkages between carbohydrates as well as N-/O-glycosidic linkages to proteins, and (iv) generation of inputs for the biomolecular simulation program CHARMM with the proper glycosidic linkage setup. In addition, Glycan Reader is linked to other functional modules in CHARMM-GUI, allowing users to easily generate carbohydrate or glycoprotein molecular simulation systems in solution or membrane environments and visualize the electrostatic potential on glycoprotein surfaces. These tools are useful for studying the impact of glycosylation on protein structure and dynamics.
Molecular Dynamics; Electrostatic Surface; Membrane; Visualization
Discrete molecular dynamics (DMD) is a rapid sampling method used in protein folding and aggregation studies. Until now, DMD was used to perform simulations of simplified protein models in conjunction with structure-based force fields. Here, we develop an all-atom protein model and a transferable force field featuring packing, solvation, and environment-dependent hydrogen bond interactions. Using the replica exchange method, we perform folding simulations of six small proteins (20–60 residues) with distinct native structures. In all cases, native or near-native states are reached in simulations. For three small proteins, multiple folding transitions are observed and the computationally-characterized thermodynamics are in quantitative agreement with experiments. The predictive power of all-atom DMD highlights the importance of environment-dependent hydrogen bond interactions in modeling protein folding. The developed approach can be used for accurate and rapid sampling of conformational spaces of proteins and protein-protein complexes, and applied to protein engineering and design of protein-protein interactions.
ab initio protein folding; environment-dependent hydrogen bond; replica exchange; free energy landscape; conformational sampling
A pathogenetic feature of Alzhemier disease is the aggregation of monomeric β-amyloid proteins (Aβ) to form oligomers. Usually these oligomers of long peptides aggregate on time scales of microseconds or longer, making computational studies using atomistic molecular dynamics models prohibitively expensive and making it essential to develop computational models that are cheaper and at the same time faithful to physical features of the process. We benchmark the ability of our implicit solvent model to describe equilibrium and dynamic properties of monomeric Aβ(10–35) using all-atom Langevin dynamics (LD) simulations since Aβ(10–35) is the only fragment whose monomeric properties have been measured. The accuracy of the implicit solvent model is tested by comparing its predictions with experiment and with those from a new explicit water MD simulation, (performed using CHARMM and the TIP3P water model) which is ~200 times slower than the implicit water simulations. The dependence on force field is investigated by running multiple trajectories for Aβ(10–35) using the CHARMM, OPLS-aal, and GS-AMBER94 force fields, while the convergence to equilibrium is tested for each force field by beginning separate trajectories from the native NMR structure, a completely stretched structure, and from unfolded initial structures. The NMR order parameter S2 is computed for each trajectory and is compared with experimental data to assess the best choice for treating aggregates of Aβ. The results vary significantly with force field. Explicit and implicit solvent simulations using the CHARMM force fields display excellent agreement with each other and once again support the accuracy of the implicit solvent model. Aβ(10–35) exhibits great flexibility, consistent with experiment data for the monomer in solution, while maintaining a general strand-loop-strand motif with a solvent exposed hydrophobic patch that is believed to be important for aggregation. Finally, equilibration of the peptide structure requires an implicit solvent LD simulation as long as 30 ns.
β-amyloid; implicit solvent; protein folding; all-atom simulations
Multiscale modeling is essential to integrating knowledge of human physiology starting from genomics, molecular biology, and the environment through the levels of cells, tissues, and organs all the way to integrated systems behavior. The lowest levels concern biophysical and biochemical events. The higher levels of organization in tissues, organs, and organism are complex, representing the dynamically varying behavior of billions of cells interacting together. Models integrating cellular events into tissue and organ behavior are forced to resort to simplifications to minimize computational complexity, thus reducing the model’s ability to respond correctly to dynamic changes in external conditions. Adjustments at protein and gene regulatory levels shortchange the simplified higher-level representations. Our cell primitive is composed of a set of subcellular modules, each defining an intracellular function (action potential, tricarboxylic acid cycle, oxidative phosphorylation, glycolysis, calcium cycling, contraction, etc.), composing what we call the “eternal cell,” which assumes that there is neither proteolysis nor protein synthesis. Within the modules are elements describing each particular component (i.e., enzymatic reactions of assorted types, transporters, ionic channels, binding sites, etc.). Cell subregions are stirred tanks, linked by diffusional or transporter-mediated exchange. The modeling uses ordinary differential equations rather than stochastic or partial differential equations. This basic model is regarded as a primitive upon which to build models encompassing gene regulation, signaling, and long-term adaptations in structure and function. During simulation, simpler forms of the model are used, when possible, to reduce computation. However, when this results in error, the more complex and detailed modules and elements need to be employed to improve model realism. The processes of error recognition and of mapping between different levels of model form complexity are challenging but are essential for successful modeling of large-scale systems in reasonable time. Currently there is to this end no established methodology from computational sciences.
cardiac metabolic systems modeling; constraint-based analysis; energetics; multicellular tissues; oxidative phosphorylation
An influx of experimental and theoretical studies of ion transport protein structure has inspired efforts to understand underlying determinants of ionic selectivity. Design principles for selective ion binding can be effectively isolated and interrogated using simplified models composed of a single ion surrounded by a set of ion-ligating molecular species. While quantum mechanical treatments of such systems naturally incorporate electronic degrees of freedom, their computational overhead typically prohibits thorough dynamic sampling of configurational space, and thus, requires approximations when determining ion-selective free energy. As an alternative, we employ dynamical simulations with a polarizable force field to probe the structure and K+/Na+ selectivity in simple models composed of one central K+/Na+ ion surrounded by 0–8 identical model compounds – N-methylacetamide, formamide, or water. In the absence of external restraints, these models represent gas-phase clusters displaying relaxed coordination structures with low coordination number. Such systems display Na+ selectivity when composed of more than ~3 organic carbonyl-containing compounds, and always display K+ selectivity when composed of water molecules. Upon imposing restraints that solely enforce specific coordination numbers, we find all models are K+-selective when ~7–8-fold ion coordination is achieved. However, when models composed of the organic compounds provide ~4–6-fold coordination, they retain their Na+-selectivity. From these trends, design principles emerge that are of basic importance in the behavior of K+ channel selectivity filters, and suggest a basis not only for K+ selectivity, but also modulation of block and closure by smaller ions.
Fibrillar aggregates of misfolded amyloid proteins are involved in a variety of diseases such as Alzheimer disease (AD), type 2 diabetes, Parkinson, Huntington and prion-related diseases. In the case of AD amyloid β (Aβ) peptides, the toxicity of amyloid oligomers and larger fibrillar aggregates is related to perturbing the biological function of the adjacent cellular membrane. We used atomistic molecular dynamics (MD) simulations of Aβ9–40 fibrillar oligomers modeled as protofilament segments, including lipid bilayers and explicit water molecules, to probe the first steps in the mechanism of Aβ-membrane interactions. Our study identified the electrostatic interaction between charged peptide residues and the lipid headgroups as the principal driving force that can modulate the further penetration of the C-termini of amyloid fibrils or fibrillar oligomers into the hydrophobic region of lipid membranes. These findings advance our understanding of the detailed molecular mechanisms and the effects related to Aβ-membrane interactions, and suggest a polymorphic structural character of amyloid ion channels embedded in lipid bilayers. While inter-peptide hydrogen bonds leading to the formation of β-strands may still play a stabilizing role in amyloid channel structures, these may also present a significant helical content in peptide regions (e.g., termini) that are subject to direct interactions with lipids rather than with neighboring Aβ peptides.
Alzheimer disease; Aβ fibrillar oligomers; Aβ peptide fibrils; Aβ protofilaments; amyloid channels; structural polymorphism of amyloid aggregates
Protein interactions support cell organization and mediate its response to any specific stimulus. Recent technological advances have produced large data-sets that aim at describing the cell interactome. These data are usually presented as graphs where proteins (nodes) are linked by edges to their experimentally determined partners. This representation reveals that protein-protein interaction (PPI) networks, like other kinds of complex networks, are not randomly organized and display properties that are typical of "hierarchical" networks, combining modularity and local clustering to scale free topology. However informative, this representation is static and provides no clue about the dynamic nature of protein interactions inside the cell.
To fill this methodological gap, we designed and implemented a computer model that captures the discrete and stochastic nature of protein interactions. In ProtNet, our simplified model, the intracellular space is mapped onto either a two-dimensional or a three-dimensional lattice with each lattice site having a linear size (5 nm) comparable to the diameter of an average globular protein. The protein filled lattice has an occupancy (e.g. 20%) compatible with the estimated crowding of proteins in the cell cytoplasm. Proteins or protein complexes are free to translate and rotate on the lattice that represents a sort of naïve unstructured cell (devoid of compartments). At each time step, molecular entities (proteins or complexes) that happen to be in neighboring cells may interact and form larger complexes or dissociate depending on the interaction rules defined in an experimental protein interaction network. This whole procedure can be seen as a sort of "discrete molecular dynamics" applied to interacting proteins in a cell.
We have tested our model by performing different simulations using as interaction rules those derived from an experimental interactome of Saccharomyces cerevisiae (1378 nodes, 2491 edges) and we have compared the dynamics of complex formation in a two and a three dimensional lattice model.
ProtNet is a cellular automaton model, where each protein molecule or complex is explicitly represented and where simple interaction rules are applied to populations of discrete particles. This tool can be used to simulate the dynamics of protein interactions in the cell.
Virus replication in the host proceeds by chains of interactions between viral and host proteins. The interactions are deeply influenced by host immune molecules and anti-viral compounds, as well as by mutations in viral proteins. To understand how these interactions proceed mechanically and how they are influenced by mutations, one needs to know the structures and dynamics of the proteins. Molecular dynamics (MD) simulation is a powerful computational method for delineating motions of proteins at an atomic-scale via theoretical and empirical principles in physical chemistry. Recent advances in the hardware and software for biomolecular simulation have rapidly improved the precision and performance of this technique. Consequently, MD simulation is quickly extending the range of applications in biology, helping to reveal unique features of protein structures that would be hard to obtain by experimental methods alone. In this review, we summarize the recent advances in MD simulations in the study of virus–host interactions and evolution, and present future perspectives on this technique.
MD simulation; viral protein; three-dimensional structure; protein dynamics; coarse-grained MD
Recently, the structure, function, stability, and dynamics of subcellular structures, organelles, and multi-protein complexes have emerged as a leading interest in structural biology. Geometric modeling not only provides visualizations of shapes for large biomolecular complexes but also fills the gap between structural information and theoretical modeling, and enables the understanding of function, stability, and dynamics. This paper introduces a suite of computational tools for volumetric data processing, information extraction, surface mesh rendering, geometric measurement, and curvature estimation of biomolecular complexes. Particular emphasis is given to the modeling of cryo-electron microscopy data. Lagrangian-triangle meshes are employed for the surface presentation. On the basis of this representation, algorithms are developed for surface area and surface-enclosed volume calculation, and curvature estimation. Methods for volumetric meshing have also been presented. Because the technological development in computer science and mathematics has led to multiple choices at each stage of the geometric modeling, we discuss the rationales in the design and selection of various algorithms. Analytical models are designed to test the computational accuracy and convergence of proposed algorithms. Finally, we select a set of six cryo-electron microscopy data representing typical subcellular complexes to demonstrate the efficacy of the proposed algorithms in handling biomolecular surfaces and explore their capability of geometric characterization of binding targets. This paper offers a comprehensive protocol for the geometric modeling of subcellular structures, organelles, and multiprotein complexes.
macromolecules; geometric modeling; Laplace–Beltrami operator; high-order geometric PDEs; surface meshing; Gaussian curvature; mean curvature
Molecular dynamics (MD) simulation is a well-established method for studying protein motion at the atomic scale. However, it is computationally intensive and generates massive amounts of data. One way of addressing the dual challenges of computation efficiency and data analysis is to construct simplified models of long-timescale protein motion from MD simulation data. In this direction, we propose to use Markov models with hidden states, in which the Markovian states represent potentially overlapping probabilistic distributions over protein conformations. We also propose a principled criterion for evaluating the quality of a model by its ability to predict long-timescale protein motions. Our method was tested on 2D synthetic energy landscapes and two extensively studied peptides, alanine dipeptide and the villin headpiece subdomain (HP-35 NleNle). One interesting finding is that although a widely accepted model of alanine dipeptide contains six states, a simpler model with only three states is equally good for predicting long-timescale motions. We also used the constructed Markov models to estimate important kinetic and dynamic quantities for protein folding, in particular, mean first-passage time. The results are consistent with available experimental measurements.
To analyze the vast number and variety of microorganisms inhabiting the human intestine, emerging metagenomic technologies are extremely powerful. The intestinal microbes are taxonomically complex and constitute an ecologically dynamic community (microbiota) that has long been believed to possess a strong impact on human physiology. Furthermore, they are heavily involved in the maturation and proliferation of human intestinal cells, helping to maintain their homeostasis and can be causative of various diseases, such as inflammatory bowel disease and obesity. A simplified animal model system has provided the mechanistic basis for the molecular interactions that occur at the interface between such microbes and host intestinal epithelia. Through metagenomic analysis, it is now possible to comprehensively explore the genetic nature of the intestinal microbiome, the mutually interacting system comprising the host cells and the residing microbial community. The human microbiome project was recently launched as an international collaborative research effort to further promote this newly developing field and to pave the way to a new frontier of human biology, which will provide new strategies for the maintenance of human health.
microbiome; microbiota; gut; metagenomics
Biochemical systems biology augments more traditional disciplines, such as genomics, biochemistry and molecular biology, by championing (i) mathematical and computational modeling; (ii) the application of traditional engineering practices in the analysis of biochemical systems; and in the past decade increasingly (iii) the use of near-comprehensive data sets derived from ‘omics platform technologies, in particular “downstream” technologies relative to genome sequencing, including transcriptomics, proteomics and metabolomics. The future progress in understanding biological principles will increasingly depend on the development of temporal and spatial analytical techniques that will provide high-resolution data for systems analyses. To date, particularly successful were strategies involving (a) quantitative measurements of cellular components at the mRNA, protein and metabolite levels, as well as in vivo metabolic reaction rates, (b) development of mathematical models that integrate biochemical knowledge with the information generated by high-throughput experiments, and (c) applications to microbial organisms. The inevitable role bioinformatics plays in modern systems biology puts mathematical and computational sciences as an equal partner to analytical and experimental biology. Furthermore, mathematical and computational models are expected to become increasingly prevalent representations of our knowledge about specific biochemical systems.
General principles governing biomolecular interactions between species are expected to differ significantly from known principles governing the interactions within species, yet these principles remain poorly understood at the systems level. A key reason for this knowledge gap is the lack of a detailed three-dimensional (3D), atomistic view of biomolecular interaction networks between species. Recent progress in structural biology, systems biology, and computational biology has enabled accurate and large-scale construction of 3D structural models of nodes and edges for protein–protein interaction networks within and between species. The resulting within- and between-species structural interaction networks have provided new biophysical, functional, and evolutionary insights into species interactions and infectious disease. Here, we review the nascent field of between-species structural systems biology, focusing on interactions between host and pathogens such as viruses.
structural systems biology; protein–protein interaction; host–pathogen interaction; bioinformatics and computational biology; network biology
A novel hybrid continuum-discrete model to simulate tumour growth on a cellular scale is proposed. The lattice-based spatiotemporal model consists of reaction-diffusion equations that describe interactions between cancer cells and their microenvironment. The fundamental ingredients that are typically considered are the nutrient concentration, the extracellular matrix (ECM), and matrix degrading enzymes (MDEs). The in vivo processes are very complex and occur on different levels. This in turn leads to huge computational costs. The main contribution of the present work is therefore to describe the processes on the basis of simplified mathematical approaches, which, at the same time, depict realistic results to understand the biological processes. In this work, we discuss if we have to simulate the MDE or if the degraded matrix can be estimated directly with respect to the cancer cell distribution. Additionally, we compare the results for modelling tumour growth using the common and our simplified approach, thereby demonstrating the advantages of the proposed method. Therefore, we introduce variations of the positioning of the nutrient delivering blood vessels and use different initializations of the ECM. We conclude that the novel method, which does not explicitly model the matrix degrading
enzymes, provides means for a straightforward and fast implementation for modelling tumour growth.
Discrete molecular dynamics simulation (DMD) uses simplified and discretized models enabling simulations to advance by event rather than by timestep. DMD is an instance of discrete event simulation and so is difficult to scale: even in this multi-core era, all reported DMD codes are serial. In this paper we discuss the inherent difficulties of scaling DMD and present our method of parallelizing DMD through event-based decomposition. Our method is microarchitecture inspired: speculative processing of events exposes parallelism, while in-order commitment ensures correctness. We analyze the potential of this parallelization method for shared-memory multiprocessors. Achieving scalability required extensive experimentation with scheduling and synchronization methods to mitigate serialization. The speed-up achieved for a variety of system sizes and complexities is nearly 6× on an 8-core and over 9× on a 12-core processor. We present and verify analytical models that account for the achieved performance as a function of available concurrency and architectural limitations.
Parallel discrete molecular dynamics; parallel discrete event simulation; parallel processing
Stochastic simulation of gene networks by Markov processes has important applications in molecular biology. The complexity of exact simulation algorithms scales with the number of discrete jumps to be performed. Approximate schemes reduce the computational time by reducing the number of simulated discrete events. Also, answering important questions about the relation between network topology and intrinsic noise generation and propagation should be based on general mathematical results. These general results are difficult to obtain for exact models.
We propose a unified framework for hybrid simplifications of Markov models of multiscale stochastic gene networks dynamics. We discuss several possible hybrid simplifications, and provide algorithms to obtain them from pure jump processes. In hybrid simplifications, some components are discrete and evolve by jumps, while other components are continuous. Hybrid simplifications are obtained by partial Kramers-Moyal expansion [1-3] which is equivalent to the application of the central limit theorem to a sub-model. By averaging and variable aggregation we drastically reduce simulation time and eliminate non-critical reactions. Hybrid and averaged simplifications can be used for more effective simulation algorithms and for obtaining general design principles relating noise to topology and time scales. The simplified models reproduce with good accuracy the stochastic properties of the gene networks, including waiting times in intermittence phenomena, fluctuation amplitudes and stationary distributions. The methods are illustrated on several gene network examples.
Hybrid simplifications can be used for onion-like (multi-layered) approaches to multi-scale biochemical systems, in which various descriptions are used at various scales. Sets of discrete and continuous variables are treated with different methods and are coupled together in a physically justified approach.
In recent years, cryo-electron microscopy (cryo-EM) has established itself as a key method in structural biology, permitting the structural characterization of large biomolecular complexes in various functional states. The data obtained through single-particle cryo-EM has recently seen a leap in resolution thanks to landmark advances in experimental and computational techniques, resulting in sub-nanometer resolution structures being obtained routinely. The remaining gap between these data and revealing the mechanisms of molecular function can be closed through hybrid modeling tools that incorporate known atomic structures into the cryo-EM data. One such tool, molecular dynamics flexible fitting (MDFF), uses molecular dynamics simulations to combine structures from X-ray crystallography with cryo-EM density maps to derive atomic models of large biomolecular complexes. The structures furnished by MDFF can be used subsequently in computational investigations aimed at revealing the dynamics of the complexes under study. In the present work, recent applications of MDFF are presented, including the interpretation of cryo-EM data of the ribosome at different stages of translation and the structure of a membrane-curvature-inducing photosynthetic complex.
MDFF; flexible fitting; cryo-EM; X-ray crystallography; NAMD; VMD; docking; hybrid modeling
Computational methods have been used in biology for sequence analysis (bioinformatics), all-atom simulation (molecular dynamics and quantum calculations), and more recently for modeling biological networks (systems biology). Of these three techniques, all-atom simulation is currently the most computationally demanding, in terms of compute load, communication speed, and memory load. Breakthroughs in electrostatic force calculation and dynamic load balancing have enabled molecular dynamics simulations of large biomolecular complexes. Here, we report simulation results for the ribosome, using approximately 2.64 million atoms, the largest all-atom biomolecular simulation published to date. Several other nanoscale systems with different numbers of atoms were studied to measure the performance of the NAMD molecular dynamics simulation program on the Los Alamos National Laboratory Q Machine. We demonstrate that multimillion atom systems represent a 'sweet spot' for the NAMD code on large supercomputers. NAMD displays an unprecedented 85% parallel scaling efficiency for the ribosome system on 1024 CPUs. We also review recent targeted molecular dynamics simulations of the ribosome that prove useful for studying conformational changes of this large biomolecular complex in atomic detail.
molecular dynamics simulation; ribosome; RNA; high performance computing
A protein’s flexibility is well recognized to underlie its capacity to engage in critical functions, such as signal transduction, biomolecular transport and biochemical reactivity. Molecular recognition is also tightly linked to the dynamics of the binding partners, yet protein flexibility has largely been ignored by the growing field of structure-based drug design (SBDD). In combination with experimentally determined structures, a number of computational methods have been proposed to model protein movements, which may be important for small molecule binding. Such techniques have the ability to expose new binding site conformations, which may in turn recognize and lead to the discovery of more potent and selective drugs through molecular docking. In this article, we discuss various methods and focus on the Relaxed Complex Scheme (RCS), which uses Molecular Dynamics (MD) simulations to model full protein flexibility and enhance virtual screening programmes. We review practical applications of the RCS and use a recent study of the HIV-1 reverse transcriptase to illustrate the various phases of the scheme. We also discuss some encouraging developments, aimed at addressing current weaknesses of the RCS.
Background and Aims
Epidemiological simulation models coupling plant growth with the dispersal and disease dynamics of an airborne plant pathogen were devised for a better understanding of host–pathogen dynamic interactions and of the capacity of grapevine development to modify the progress of powdery mildew epidemics.
The first model is a complex discrete mechanistic model (M-model) that explicitly incorporates the dynamics of host growth and the development and dispersion of the pathogen at the vine stock scale. The second model is a simpler ordinary differential equations (ODEs) compartmental SEIRT model (C-model) handling host growth (foliar surface) and the ontogenic resistance of the leaves. With the M-model various levels of vine development are simulated under three contrasting climatic scenarios and the relationship between host and disease variables are examined at key periods in the epidemic process. The ability of the C-model to retrieve the main dynamics of the disease for a range of vine growth given by the M-model is investigated.
The M-model strengthens experimental results observed regarding the effect of the rate of leaf emergence and of the number of leaves at flowering on the severity of the disease. However, it also underlines strong variations of the dynamics of disease depending on the vigour and indirectly on the climatic scenarios. The C-model could be calibrated by using the M-model provided that different parameters before and after shoot topping and for various vigour levels and inoculation time are used. Biologically relevant estimations of the parameters that could be used for its extension to the vineyard scale are obtained.
The M-model is able to generate a wide range of growth scenarios with a strong impact on disease evolution. The C-model is a promising tool to be used at a larger scale.
Host–pathogen models; mechanistic model; SEIRT model; host growth; powdery mildew; grapevine