scholarly journals Validation of DBFOLD: An efficient algorithm for computing folding pathways of complex proteins

2020 ◽  
Vol 16 (11) ◽  
pp. e1008323
Author(s):  
Amir Bitran ◽  
William M. Jacobs ◽  
Eugene Shakhnovich
Keyword(s):  
Monte Carlo ◽  
Protein Folding ◽  
Detailed Balance ◽  
Computation Time ◽  
Enhanced Sampling ◽  
Computational Speed ◽  
Wide Range ◽  
Folding Pathways ◽  
Time Required

Atomistic simulations can provide valuable, experimentally-verifiable insights into protein folding mechanisms, but existing ab initio simulation methods are restricted to only the smallest proteins due to severe computational speed limits. The folding of larger proteins has been studied using native-centric potential functions, but such models omit the potentially crucial role of non-native interactions. Here, we present an algorithm, entitled DBFOLD, which can predict folding pathways for a wide range of proteins while accounting for the effects of non-native contacts. In addition, DBFOLD can predict the relative rates of different transitions within a protein’s folding pathway. To accomplish this, rather than directly simulating folding, our method combines equilibrium Monte-Carlo simulations, which deploy enhanced sampling, with unfolding simulations at high temperatures. We show that under certain conditions, trajectories from these two types of simulations can be jointly analyzed to compute unknown folding rates from detailed balance. This requires inferring free energies from the equilibrium simulations, and extrapolating transition rates from the unfolding simulations to lower, physiologically-reasonable temperatures at which the native state is marginally stable. As a proof of principle, we show that our method can accurately predict folding pathways and Monte-Carlo rates for the well-characterized Streptococcal protein G. We then show that our method significantly reduces the amount of computation time required to compute the folding pathways of large, misfolding-prone proteins that lie beyond the reach of existing direct simulation. Our algorithm, which is available online, can generate detailed atomistic models of protein folding mechanisms while shedding light on the role of non-native intermediates which may crucially affect organismal fitness and are frequently implicated in disease.

scholarly journals DBFOLD: An efficient algorithm for computing folding pathways of complex proteins

2020 ◽  
Author(s):  
Amir Bitran ◽  
William M. Jacobs ◽  
Eugene Shakhnovich
Keyword(s):  
Monte Carlo ◽  
Protein Folding ◽  
Detailed Balance ◽  
Simulation Methods ◽  
Free Energies ◽  
Native State ◽  
Folding Rates ◽  
Computational Speed ◽  
Folding Pathways

AbstractAtomistic simulations can provide valuable, experimentally-verifiable insights into protein folding mechanisms, but existing ab initio simulation methods are restricted to only the smallest proteins due to severe computational speed limits. The folding of larger proteins has been studied using native-centric potential functions, but such models omit the potentially crucial role of non-native interactions.Here, we present an algorithm, entitled DBFOLD, which can predict folding pathways for a wide range of proteins while accounting for the effects of non-native contacts. In addition, DBFOLD can predict the relative rates of different transitions within a protein’s folding pathway. To accomplish this, rather than directly simulating folding, our method combines equilibrium Monte-Carlo simulations, which deploy enhanced sampling, with unfolding simulations at high temperatures. We show that under certain conditions, trajectories from these two types of simulations can be jointly analyzed to compute unknown folding rates from detailed balance. This requires inferring free energies from the equilibrium simulations, and extrapolating transition rates from the unfolding simulations to lower, physiologically-reasonable temperatures at which the native state is marginally stable. As a proof of principle, we show that our method can accurately predict folding pathways and Monte-Carlo rates for the well-characterized Streptococcal protein G. We then show that our method significantly reduces the amount of computation time required to compute the folding pathways of large, misfolding-prone proteins that lie beyond the reach of existing direct simulation methods. Our algorithm, which is available online, can generate detailed atomistic models of protein folding mechanisms while shedding light on the role of non-native intermediates which may crucially affect organismal fitness and are frequently implicated in disease.Author summaryMany proteins must adopt a specific structure in order to function. Computational simulations have been used to shed light on the mechanisms of protein folding, but unfortunately, realistic simulations can typically only be run for small proteins, due to severe limits in computational speed. Here, we present a method to solve this problem, whereby instead of directly simulating folding from an unfolded state, we run simulations that allow for computation of equilibrium folding free energies, alongside high temperature simulations to compute unfolding rates. From these quantities, folding rates can be computed using detailed balance. Importantly, our method can account for the effects of nonnative contacts which transiently form during folding and must be broken prior to adoption of the native state. Such contacts, which are often excluded from simple models of folding, may crucially affect real protein folding pathways and are often observed in folding intermediates implicated in disease.

Modeling of Size Effects in Diffusion Driven Processes at Nanoscale - Large Atomic and Mesoscale Methods

2017 ◽  
Vol 12 ◽  
pp. 38-73
Author(s):  
Tomasz Wejrzanowski ◽  
Krzysztof Jan Kurzydlowski
Keyword(s):  
Molecular Dynamics ◽  
Monte Carlo ◽  
Free Surface ◽  
Size Effects ◽  
Experimental Studies ◽  
High Energy ◽  
Intergranular Phase ◽  
Wide Range ◽  
Microstructure Effect

The results of the studies presented here are devoted to understanding of microstructure effect on the processes and properties driven by diffusion. The role of various interfaces (intergranular, phase, free surface), as the high-energy defects, is underlined and investigated with special attention. The methodology relevant to analyses of the microstructural processes is first briefly presented. The capability and limitations of classical molecular dynamics, mesoscale Monte Carlo and cellular automaton techniques are described. Two examples of the diffusion driven processes analyzed at various length and time scale are shown: namely, grain growth in nanometallic materials and melting of thin embedded films. The modeling results are also accompanied with experimental studies. Thanks to application of numerical methods, models of relevant processes were proposed, which enabled to provide quantitative relationships between microstructure and the process kinetics. Such relationships can be later used for design of optimized materials for wide range of applications.

scholarly journals MECHANISMS INVOLVED IN FIBRIN FORMATION

1951 ◽  
Vol 34 (5) ◽  
pp. 493-513 ◽  
Author(s):  
Paul W. Boyles ◽  
John H. Ferguson ◽  
Paul H. Muehlke
Keyword(s):  
Two Stage ◽  
Fibrin Formation ◽  
Technical Requirements ◽  
Wide Range ◽  
High Dilutions ◽  
Partial Denaturation ◽  
Ion Effects ◽  
Time Required ◽  
Latent Phase

That the role of thrombin in the conversion of fibrinogen to fibrin is essentially enzymatic, is established not only by the minute amounts of thrombin which are effective but also by the complete independence of fibrin yields and thrombin concentrations over a very wide range of thrombin dilutions and clotting times. The thrombin-fibrinogen reaction, in the phase beyond the "latent period" at least, seems fundamentally "first order." Technical requirements of the experiments leading to these conclusions include: (1) a highly purified (e.g. 97 per cent "clottable") fibrinogen, (2) absence of traces of thrombic impurities in the fibrinogen, (3) absence of fibrinolytic protease contaminant of the thrombin and the fibrinogen, and (4) sufficient stability of the thrombin even at very high dilutions. Four conditions affecting thrombin stability have been investigated. Fibrin yields are not significantly modified by numerous experimental circumstances that influence the clotting time, such as (1) temperature, (2) pH, (3) non-specific salt action due to electrical (ionic) charges, which alter the Coulomb forces involved in the fibrillar aggregation, (4) specific ion effects, whether clot-accelerating (e.g. Ca++) or clot-inhibitory (e.g. Fe(CN)6''''), (5) occluding (adsorptive) colloids, which have a "fibrinoplastic" action, e.g. (a) acacia and probably (b) fibrinogen which has been mildly "denatured" by salt-heating, acidification, etc. The data with which several European workers have attempted to substantiate the idea of a two-stage thrombin-fibrinogen reaction with an intermediary "profibrin" (allegedly partly "denatured") have been reanalyzed with controls which lead us to very different conclusions, viz. (1) denaturation and fibrin formation are independent; (2) partial denaturation is "fibrinoplastic" (see above); and (3) conditions of strong salinity and acid pH (5.1) usually do not completely prevent the thrombin-fibrinogen reaction but merely prolong the "latent" phase and lessen the time required for completion of essentially the same reaction (fibrin polymerization) when more favorable clotting conditions are restored. Thus, our experiments advance the modern concepts concerning the coagulation mechanisms along lines that, for the most part, agree with those of the Harvard physical chemists, and we oppose the European views concerning a two-stage reaction, "profibrin," and "the denaturase theory" of clotting.

scholarly journals Modelling and optimization of computer network traffic controllers

2005 ◽  
Vol 2005 (6) ◽  
pp. 617-640 ◽  
Author(s):  
N. U. Ahmed ◽  
Bo Li ◽  
Luis Orozco-Barbosa
Keyword(s):  
Genetic Algorithm ◽  
Network Traffic ◽  
Computer Network ◽  
Formal Model ◽  
Computation Time ◽  
Wide Range ◽  
Token Bucket ◽  
Speed Up ◽  
Genetic Algorithm Approach ◽  
Time Required

During the past years, there has been increasing interest in the design and development of network traffic controllers capable of ensuring the QoS requirements of a wide range of applications. In this paper, we construct a dynamic model for the token-bucket algorithm: a traffic controller widely used in various QoS-aware protocol architectures. Based on our previous work, we use a system approach to develop a formal model of the traffic controller. This model serves as a basis to formally specify and evaluate the operation of the token-bucket algorithm. Then we develop an optimization algorithm based on a dynamic programming and genetic algorithm approach. We conduct an extensive campaign of numerical experiments allowing us to gain insight on the operation of the controller and evaluate the benefits of using a genetic algorithm approach to speed up the optimization process. Our results show that the use of the genetic algorithm proves particularly useful in reducing the computation time required to optimize the operation of a system consisting of multiple token-bucket-regulated sources.

scholarly journals Parallel G-triplexes and G-hairpins as potential transitory ensembles in the folding of parallel-stranded DNA G-Quadruplexes

2019 ◽  
Vol 47 (14) ◽  
pp. 7276-7293 ◽  
Author(s):  
Petr Stadlbauer ◽  
Petra Kührová ◽  
Lukáš Vicherek ◽  
Pavel Banáš ◽  
Michal Otyepka ◽  
...  
Keyword(s):  
Single Molecule ◽  
Local Equilibrium ◽  
Enhanced Sampling ◽  
Loop Formation ◽  
Folding Intermediates ◽  
G4 Dna ◽  
Folding Pathways ◽  
Dynamics Simulations ◽  
Genomic Regions

Abstract Guanine quadruplexes (G4s) are non-canonical nucleic acids structures common in important genomic regions. Parallel-stranded G4 folds are the most abundant, but their folding mechanism is not fully understood. Recent research highlighted that G4 DNA molecules fold via kinetic partitioning mechanism dominated by competition amongst diverse long-living G4 folds. The role of other intermediate species such as parallel G-triplexes and G-hairpins in the folding process has been a matter of debate. Here, we use standard and enhanced-sampling molecular dynamics simulations (total length of ∼0.9 ms) to study these potential folding intermediates. We suggest that parallel G-triplex per se is rather an unstable species that is in local equilibrium with a broad ensemble of triplex-like structures. The equilibrium is shifted to well-structured G-triplex by stacked aromatic ligand and to a lesser extent by flanking duplexes or nucleotides. Next, we study propeller loop formation in GGGAGGGAGGG, GGGAGGG and GGGTTAGGG sequences. We identify multiple folding pathways from different unfolded and misfolded structures leading towards an ensemble of intermediates called cross-like structures (cross-hairpins), thus providing atomistic level of description of the single-molecule folding events. In summary, the parallel G-triplex is a possible, but not mandatory short-living (transitory) intermediate in the folding of parallel-stranded G4.

Monte Carlo Simulation of the Growth of ZnSe by MBE

1986 ◽  
Vol 77 ◽  
Author(s):  
R. Venkatasubramanian ◽  
N. Otsuka ◽  
S. Datta ◽  
L. A. Kolodziejski ◽  
R. L. Gunshor
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Molecular Beam ◽  
Flux Ratio ◽  
Monte Carlo Study ◽  
The Other ◽  
Structural Quality ◽  
Wide Range

ABSTRACTA Monte Carlo study of the growth of ZnSe by Molecular beam epitaxy is presented. The study is focused on the role of surface kinetic reactions on the structural quality of the epilayers. Two different models for the incorporation of Se molecules, one with a highly reactive physisorbed state and the other with a relatively nonreactive physisorbed state are employed for simulations. It is shown that the structural quality of the epilayers is very sensitive to the flux ratio if the physisorbed state is relatively nonreactive. It is also shown that if the physisorbed state is highly reactive, good quality epilayers are obtained over a wide range of flux ratio.

Microwaves: Application in Electron Microscopy

1990 ◽  
Vol 48 (3) ◽  
pp. 140-141
Author(s):  
Anthony S-Y Leong ◽  
David W Gove
Keyword(s):  
Electron Microscopy ◽  
Light Microscopy ◽  
Chemical Reactions ◽  
Electromagnetic Waves ◽  
Tissue Fixation ◽  
Primary Method ◽  
Dipolar Molecules ◽  
Wide Range ◽  
Time Required ◽  
Cryostat Sections

Microwaves (MW) are electromagnetic waves which are commonly generated at a frequency of 2.45 GHz. When dipolar molecules such as water, the polar side chains of proteins and other molecules with an uneven distribution of electrical charge are exposed to such non-ionizing radiation, they oscillate through 180° at a rate of 2,450 million cycles/s. This rapid kinetic movement results in accelerated chemical reactions and produces instantaneous heat. MWs have recently been applied to a wide range of procedures for light microscopy. MWs generated by domestic ovens have been used as a primary method of tissue fixation, it has been applied to the various stages of tissue processing as well as to a wide variety of staining procedures. This use of MWs has not only resulted in drastic reductions in the time required for tissue fixation, processing and staining, but have also produced better cytologic images in cryostat sections, and more importantly, have resulted in better preservation of cellular antigens.

The Problem of Identifying and Modeling the Relationship between Monetary Factor and Inflation in the Russian Economy

2008 ◽  
pp. 61-76
Author(s):  
A. Porshakov ◽  
A. Ponomarenko
Keyword(s):  
Money Supply ◽  
Money Demand ◽  
Russian Economy ◽  
Long Run ◽  
Complex Approach ◽  
Wide Range ◽  
Long Time ◽  
The Relationship ◽  
Supply Side Factors

The role of monetary factor in generating inflationary processes in Russia has stimulated various debates in social and scientific circles for a relatively long time. The authors show that identification of the specificity of relationship between money and inflation requires a complex approach based on statistical modeling and involving a wide range of indicators relevant for the price changes in the economy. As a result a model of inflation for Russia implying the decomposition of inflation dynamics into demand-side and supply-side factors is suggested. The main conclusion drawn is that during the recent years the volume of inflationary pressures in the Russian economy has been determined by the deviation of money supply from money demand, rather than by money supply alone. At the same time, monetary factor has a long-run spread over time impact on inflation.

Introduction: Emotion, History and the Arts

2018 ◽  
Vol 7 (2) ◽  
pp. 117-128 ◽  
Author(s):  
Erin Sullivan ◽  
Marie Louise Herzfeld-Schild
Keyword(s):  
Historical Change ◽  
Carson Mccullers ◽  
Emotional Life ◽  
Review Section ◽  
The Arts ◽  
Wide Range ◽  
War Correspondents ◽  
History Of ◽  
Johan Huizinga

This introduction surveys the rise of the history of emotions as a field and the role of the arts in such developments. Reflecting on the foundational role of the arts in the early emotion-oriented histories of Johan Huizinga and Jacob Burkhardt, as well as the concerns about methodological impressionism that have sometimes arisen in response to such studies, the introduction considers how intensive engagements with the arts can open up new insights into past emotions while still being historically and theoretically rigorous. Drawing on a wide range of emotionally charged art works from different times and places—including the novels of Carson McCullers and Harriet Beecher-Stowe, the private poetry of neo-Confucian Chinese civil servants, the photojournalism of twentieth-century war correspondents, and music from Igor Stravinsky to the Beatles—the introduction proposes five ways in which art in all its forms contributes to emotional life and consequently to emotional histories: first, by incubating deep emotional experiences that contribute to formations of identity; second, by acting as a place for the expression of private or deviant emotions; third, by functioning as a barometer of wider cultural and attitudinal change; fourth, by serving as an engine of momentous historical change; and fifth, by working as a tool for emotional connection across communities, both within specific time periods but also across them. The introduction finishes by outlining how the special issue's five articles and review section address each of these categories, while also illustrating new methodological possibilities for the field.

Short Films from a Small Nation

2018 ◽  
Author(s):  
C. Claire Thomson
Keyword(s):  
Public Information ◽  
Industrial Process ◽  
Actor Network Theory ◽  
Documentary Films ◽  
Wide Range ◽  
Short Films ◽  
Post War ◽  
The 1960S ◽  
Art And Architecture

The first book-length study in English of a national corpus of state-sponsored informational film, this book traces how Danish shorts on topics including social welfare, industry, art and architecture were commissioned, funded, produced and reviewed from the inter-war period to the 1960s. For three decades, state-sponsored short filmmaking educated Danish citizens, promoted Denmark to the world, and shaped the careers of renowned directors like Carl Th. Dreyer. Examining the life cycle of a representative selection of films, and discussing their preservation and mediation in the digital age, this book presents a detailed case study of how informational cinema is shaped by, and indeed shapes, its cultural, political and technological contexts.The book combines close textual analysis of a broad range of films with detailed accounts of their commissioning, production, distribution and reception in Denmark and abroad, drawing on Actor-Network Theory to emphasise the role of a wide range of entities in these processes. It considers a broad range of genres and sub-genres, including industrial process films, public information films, art films, the city symphony, the essay film, and many more. It also maps international networks of informational and documentary films in the post-war period, and explores the role of informational film in Danish cultural and political history.

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