Multidimensional free energy surface of unfolding of HP-36: Microscopic origin of ruggedness

The protein folding funnel paradigm suggests that folding and unfolding proceed as directed diffusion in a multidimensional free energy surface where a multitude of pathways can be traversed during the protein's sojourn from initial to final state. However, finding even a single pathway, with the detail chronicling of intermediates, is an arduous task. In this work we explore the free energy surface of unfolding pathway through umbrella sampling, for a small globular a-helical protein chicken-villin headpiece (HP-36) when the melting of secondary structures is induced by adding DMSO in aqueous solution. We find that the unfolding proceeds through the initial separation or melting of aggregated hydrophobic core that comprises of three phenylalanine residues (Phe7, Phe11, and Phe18). This separation is accompanied by simultaneous melting of the second helix. Unfolding is found to be a multistage process involving crossing of three consecutive minima and two barriers at the initial stage. At a molecular level, Phe18 is observed to reorient itself towards other hydrophobic grooves to stabilize the intermediate states. We identify the configuration of the intermediates and correlate the intermediates with those obtained in our previous works. We also give an estimate of the barriers for different transition states and observe the softening of the barriers with increasing DMSO concentration. We show that higher concentration of DMSO tunes the unfolding pathway by destabilizing the third minimum and stabilizing the second one, indicating the development of a solvent modified, less rugged pathway. The prime outcome of this work is the demonstration that mixed solvents can profoundly transform the nature of the energy landscape and induce unfolding via a modified route. A successful application of Kramer's rate equation correlating the free energy simulation results shows faster rate of unfolding with increasing DMSO concentration. This work perhaps presents the first systematic theoretical study of the effect of a chemical denaturant on the microscopic free energy surface and rates of unfolding of HP-36. (C) 2014 AIP Publishing LLC.

Simultaneous Perturbation Newton Algorithms for Simulation Optimization

We present a new Hessian estimator based on the simultaneous perturbation procedure, that requires three system simulations regardless of the parameter dimension. We then present two Newton-based simulation optimization algorithms that incorporate this Hessian estimator. The two algorithms differ primarily in the manner in which the Hessian estimate is used. Both our algorithms do not compute the inverse Hessian explicitly, thereby saving on computational effort. While our first algorithm directly obtains the product of the inverse Hessian with the gradient of the objective, our second algorithm makes use of the Sherman-Morrison matrix inversion lemma to recursively estimate the inverse Hessian. We provide proofs of convergence for both our algorithms. Next, we consider an interesting application of our algorithms on a problem of road traffic control. Our algorithms are seen to exhibit better performance than two Newton algorithms from a recent prior work.

Computer simulation on the collision-sticking dynamics of two colloidal particles in an optical trap

Collisions of a particle pair induced by optical tweezers have been employed to study colloidal stability. In order to deepen insights regarding the collision-sticking dynamics of a particle pair in the optical trap that were observed in experimental approaches at the particle level, the authors carry out a Brownian dynamics simulation. In the simulation, various contributing factors, including the Derjaguin-Landau-Verwey-Overbeek interaction of particles, hydrodynamic interactions, optical trapping forces on the two particles, and the Brownian motion, were all taken into account. The simulation reproduces the tendencies of the accumulated sticking probability during the trapping duration for the trapped particle pair described in our previous study and provides an explanation for why the two entangled particles in the trap experience two different statuses. (c) 2007 American Institute of Physics.

A molecular dynamics study of the microscopic properties of simple dense fluids

The microscopic properties of a two-dimensional model dense fluid of Lennard-Jones disks have been studied using the so-called "molecular dynamics" method. Analyses of the computer-generated simulation data in terms of "conventional" thermodynamic and distribution functions verify the physical validity of the model and the simulation technique.

The radial distribution functions g(r) computed from the simulation data exhibit several subsidiary features rather similar to those appearing in some of the g(r) functions obtained by X-ray and thermal neutron diffraction measurements on real simple liquids. In the case of the model fluid, these "anomalous" features are thought to reflect the existence of two or more alternative configurations for local ordering.

Graphical display techniques have been used extensively to provide some intuitive insight into the various microscopic phenomena occurring in the model. For example, "snapshots" of the instantaneous system configurations for different times show that the "excess" area allotted to the fluid is collected into relatively large, irregular, and surprisingly persistent "holes". Plots of the particle trajectories over intervals of 2.0 to 6.0 x 10^-12 sec indicate that the mechanism for diffusion in the dense model fluid is "cooperative" in nature, and that extensive diffusive migration is generally restricted to groups of particles in the vicinity of a hole.

A quantitative analysis of diffusion in the model fluid shows that the cooperative mechanism is not inconsistent with the statistical predictions of existing theories of singlet, or self-diffusion in liquids. The relative diffusion of proximate particles is, however, found to be retarded by short-range dynamic correlations associated with the cooperative mechanism--a result of some importance from the standpoint of bimolecular reaction kinetics in solution.

A new, semi-empirical treatment for relative diffusion in liquids is developed, and is shown to reproduce the relative diffusion phenomena observed in the model fluid quite accurately. When incorporated into the standard Smoluchowski theory of diffusion-controlled reaction kinetics, the more exact treatment of relative diffusion is found to lower the predicted rate of reaction appreciably.

Finally, an entirely new approach to an understanding of the liquid state is suggested. Our experience in dealing with the simulation data--and especially, graphical displays of the simulation data--has led us to conclude that many of the more frustrating scientific problems involving the liquid state would be simplified considerably, were it possible to describe the microscopic structures characteristic of liquids in a concise and precise manner. To this end, we propose that the development of a formal language of partially-ordered structures be investigated.

Microscopic Origin of Macroscopic Strength in Granular Media: A Numerical and Analytical Approach

Constitutive modeling in granular materials has historically been based on macroscopic experimental observations that, while being usually effective at predicting the bulk behavior of these type of materials, suffer important limitations when it comes to understanding the physics behind grain-to-grain interactions that induce the material to macroscopically behave in a given way when subjected to certain boundary conditions.

The advent of the discrete element method (DEM) in the late 1970s helped scientists and engineers to gain a deeper insight into some of the most fundamental mechanisms furnishing the grain scale. However, one of the most critical limitations of classical DEM schemes has been their inability to account for complex grain morphologies. Instead, simplified geometries such as discs, spheres, and polyhedra have typically been used. Fortunately, in the last fifteen years, there has been an increasing development of new computational as well as experimental techniques, such as non-uniform rational basis splines (NURBS) and 3D X-ray Computed Tomography (3DXRCT), which are contributing to create new tools that enable the inclusion of complex grain morphologies into DEM schemes.

Yet, as the scientific community is still developing these new tools, there is still a gap in thoroughly understanding the physical relations connecting grain and continuum scales as well as in the development of discrete techniques that can predict the emergent behavior of granular materials without resorting to phenomenology, but rather can directly unravel the micro-mechanical origin of macroscopic behavior.

In order to contribute towards closing the aforementioned gap, we have developed a micro-mechanical analysis of macroscopic peak strength, critical state, and residual strength in two-dimensional non-cohesive granular media, where typical continuum constitutive quantities such as frictional strength and dilation angle are explicitly related to their corresponding grain-scale counterparts (e.g., inter-particle contact forces, fabric, particle displacements, and velocities), providing an across-the-scale basis for better understanding and modeling granular media.

In the same way, we utilize a new DEM scheme (LS-DEM) that takes advantage of a mathematical technique called level set (LS) to enable the inclusion of real grain shapes into a classical discrete element method. After calibrating LS-DEM with respect to real experimental results, we exploit part of its potential to study the dependency of critical state (CS) parameters such as the critical state line (CSL) slope, CSL intercept, and CS friction angle on the grain's morphology, i.e., sphericity, roundness, and regularity.

Finally, we introduce a first computational algorithm to ``clone'' the grain morphologies of a sample of real digital grains. This cloning algorithm allows us to generate an arbitrary number of cloned grains that satisfy the same morphological features (e.g., roundness and aspect ratio) displayed by their real parents and can be included into a DEM simulation of a given mechanical phenomenon. In turn, this will help with the development of discrete techniques that can directly predict the engineering scale behavior of granular media without resorting to phenomenology.

Effects of soil fabric on behaviors of granular soils: Microscopic modeling

The effects of initial soil fabric on behaviors of granular soils are investigated by using Distinct Element Method (DEM) numerical simulation. Soil specimens are represented by an assembly of non-uniform sized spheres with different initial contact normal distributions. Isotropically consolidated triaxial compression loading and extension unloading in both undrained and drained conditions are simulated for vertically- and horizontally-sheared specimens. The numerical simulation results are compared qualitatively with the published experimental data and the effects of initial soil fabric on resulting soil behaviors are discussed, including the effects of specimen reconstitution methods, effects of large preshearing, and anisotropic characteristics in undrained and drained conditions. The effects of initial soil fabric and mode of shearing on the quasi-steady state line are also investigated. The numerical simulation results can systematically explain that the observed experimental behaviors of granular soils are due principally to their conditions of the initial soil fabric. This outcome provides insights into the observed phenomena in microscopic view. © 2011 Elsevier Ltd.

Air traffic control with an expected value criterion

in this contribution we discuss a stochastic framework for air traffic conflict resolution. The conflict resolution task is posed as the problem of optimizing an expected value criterion. Optimization is carried out by Monte Carlo Markov Chain (MCMC) simulation. A numerical example illustrates the proposed strategy. Copyright © 2005 IFAC.

Monte Carlo optimization strategies for air-traffic control

The safety of the flights, and in particular conflict resolution for separation assurance, is one of the main tasks of Air Traffic Control. Conflict resolution requires decision making in the face of the considerable levels of uncertainty inherent in the motion of aircraft. We present a Monte Carlo framework for conflict resolution which allows one to take into account such levels of uncertainty through the use of a stochastic simulator. A simulation example inspired by current air traffic control practice illustrates the proposed conflict resolution strategy. Copyright © 2005 by the American Institute of Aeronautics and Astronautics, Inc. All rights reserved.

Theory and simulation in neuroscience.

Modeling work in neuroscience can be classified using two different criteria. The first one is the complexity of the model, ranging from simplified conceptual models that are amenable to mathematical analysis to detailed models that require simulations in order to understand their properties. The second criterion is that of direction of workflow, which can be from microscopic to macroscopic scales (bottom-up) or from behavioral target functions to properties of components (top-down). We review the interaction of theory and simulation using examples of top-down and bottom-up studies and point to some current developments in the fields of computational and theoretical neuroscience.

Effects of longer heavy vehicles on traffic congestion

Two-lane, "microscopic" (vehicle-by-vehicle) simulations of motorway traffic are developed using existing models and validated using measured data from the M25 motorway. An energy consumption model is also built in, which takes the logged trajectories of simulated vehicles as drive-cycles. The simulations are used to investigate the effects on motorway congestion and fuel consumption if "longer and/or heavier vehicles" (LHVs) were to be permitted in the UK. Baseline scenarios are simulated with traffic composed of cars, light goods vehicles and standard heavy goods vehicles (HGVs). A proportion of conventional articulated HGVs is then replaced by a smaller number of LHVs carrying the same total payload mass and volume. Four LHV configurations are investigated: an 18.75 m, 46 t longer semi-trailer (LST); 25.25 m, 50 t and 60 t B-doubles and a 34 m, 82 t A-double. Metrics for congestion, freight fleet energy consumption and car energy consumption are defined for comparing the scenarios. Finally, variation of take-up level and LHV engine power for the LST and A-double are investigated. It is concluded that: (a) LHVs should reduce congestion particularly in dense traffic, however, a low mean proportion of freight traffic on UK roads and low take-up levels will limit this effect to be almost negligible; (b) LHVs can significantly improve the energy efficiency of freight fleets, giving up to a 23% reduction in fleet energy consumption at high take-up levels; (c) the small reduction in congestion caused by LHVs could improve the fuel consumption of other road users by up to 3% in dense traffic, however in free-flowing traffic an opposite effect occurs due to higher vehicle speeds and aerodynamic losses; and (d) underpowered LHVs have potential to generate severe congestion, however current manufacturers' recommendations appear suitable. © 2013 IMechE.

How does solvent molecular size affect the microscopic structure in polymer solutions?

Monte Carlo simulation has been used to investigate the effects of linear solvent molecular size on polymer chain conformation in solutions. Increasing the solvent molecular size leads to shrinkage of the polymer chains and increase of the critical overlap concentrations. The root-mean-square radius of gyration of polymer chains (R-g) is less sensitive to the variation of polymer concentration in solutions of larger solvent molecules. In addition, the dependency of R-g on polymer concentration under normal solvent conditions and solvent molecular size is in good agreement with scaling laws. When the solvent molecular size approaches the ideal end-to-end distance of the polymer chain, an extra aggregation of polymer chains occurs, and the solvent becomes the so-called medium-sized solvent. When the size of solvent molecules is smaller than the medium size, the polymer chains are swollen or partially swollen. However, when the size of solvent molecules is larger than the medium size, the polymer coils shrink and segregate, enwrapped by the large solvent molecules.

Differentiated Control of Web Traffic: A Numerical Analysis

Internet measurements show that the size distribution of Web-based transactions is usually very skewed; a few large requests constitute most of the total traffic. Motivated by the advantages of scheduling algorithms which favor short jobs, we propose to perform differentiated control over Web-based transactions to give preferential service to short web requests. The control is realized through service semantics provided by Internet Traffic Managers, a Diffserv-like architecture. To evaluate the performance of such a control system, it is necessary to have a fast but accurate analytical method. To this end, we model the Internet as a time-shared system and propose a numerical approach which utilizes Kleinrock's conservation law to solve the model. The numerical results are shown to match well those obtained by packet-level simulation, which runs orders of magnitude slower than our numerical method.

Integration of micro- and macroscopic models for pedestrian evacuation simulation

Simulation of pedestrian evacuations of smart buildings in emergency is a powerful tool for building analysis, dynamic evacuation planning and real-time response to the evolving state of evacuations. Macroscopic pedestrian models are low-complexity models that are and well suited to algorithmic analysis and planning, but are quite abstract. Microscopic simulation models allow for a high level of simulation detail but can be computationally intensive. By combining micro- and macro- models we can use each to overcome the shortcomings of the other and enable new capability and applications for pedestrian evacuation simulation that would not be possible with either alone. We develop the EvacSim multi-agent pedestrian simulator and procedurally generate macroscopic flow graph models of building space, integrating micro- and macroscopic approaches to simulation of the same emergency space. By “coupling” flow graph parameters to microscopic simulation results, the graph model captures some of the higher detail and fidelity of the complex microscopic simulation model. The coupled flow graph is used for analysis and prediction of the movement of pedestrians in the microscopic simulation, and investigate the performance of dynamic evacuation planning in simulated emergencies using a variety of strategies for allocation of macroscopic evacuation routes to microscopic pedestrian agents. The predictive capability of the coupled flow graph is exploited for the decomposition of microscopic simulation space into multiple future states in a scalable manner. By simulating multiple future states of the emergency in short time frames, this enables sensing strategy based on simulation scenario pattern matching which we show to achieve fast scenario matching, enabling rich, real-time feedback in emergencies in buildings with meagre sensing capabilities.

An energy-efficient data delivery scheme for delay-sensitive traffic in wireless sensor networks

We propose a novel data-delivery method for delay-sensitive traffic that significantly reduces the energy consumption in wireless sensor networks without reducing the number of packets that meet end-to-end real-time deadlines. The proposed method, referred to as SensiQoS, leverages the spatial and temporal correlation between the data generated by events in a sensor network and realizes energy savings through application-specific in-network aggregation of the data. SensiQoS maximizes energy savings by adaptively waiting for packets from upstream nodes to perform in-network processing without missing the real-time deadline for the data packets. SensiQoS is a distributed packet scheduling scheme, where nodes make localized decisions on when to schedule a packet for transmission to meet its end-to-end real-time deadline and to which neighbor they should forward the packet to save energy. We also present a localized algorithm for nodes to adapt to network traffic to maximize energy savings in the network. Simulation results show that SensiQoS improves the energy savings in sensor networks where events are sensed by multiple nodes, and spatial and/or temporal correlation exists among the data packets. Energy savings due to SensiQoS increase with increase in the density of the sensor nodes and the size of the sensed events. © 2010 Harshavardhan Sabbineni and Krishnendu Chakrabarty.

Traffic policing in ATM networks with multimedia traffic: the super leaky bucket

Traffic policing and bandwidth management strategies at the User Network Interface (UNI) of an ATM network are investigated by simulation. The network is assumed to transport real time (RT) traffic like voice and video as well as non-real time (non-RT) data traffic. The proposed policing function, called the super leaky bucket (S-LB), is based on the leaky bucket (LB), but handles the three types of traffic differently according to their quality of service (QoS) requirements. Separate queues are maintained for RT and non-RT traffic. They are normally served alternately, but if the number of RT cells exceeds a threshold, it gets non-pre-emptive priority. Further increase of the RT queue causes low priority cells to be discarded. Non-RT cells are buffered and the sources are throttled back during periods of congestion. The simulations clearly demonstrate the advantages of the proposed strategy in providing improved levels of service (delay, jitter and loss) for all types of traffic.