The Blueprint of Logical Decisions in a NF-κB Signaling System.

Nearly identical cells can exhibit substantially different responses to the same stimulus that causes phenotype diversity. Such interplay between phenotype diversity and the architecture of regulatory circuits is crucial since it determines the state of a biological cell. Here, we theoretically analyze how the circuit blueprints of NF-κB in cellular environments are formed and their role in determining the cells' metabolic state. The NF-κB is a collective name for a developmental conserved family of five different transcription factors that can form homodimers or heterodimers and often promote DNA looping to reprogram the inflammatory gene response. The NF-κB controls many biological functions, including cellular differentiation, proliferation, migration, and survival. Our model shows that nuclear localization of NF-κB differentially promotes logic operations such as AND, NAND, NOR, and OR in its regulatory network. Through the quantitative thermodynamic model of transcriptional regulation and systematic variation of promoter-enhancer interaction modes, we can account for the origin of various logic gates as formed in the NF-κB system. We further show that the interconversion or switching of logic gates yielded under systematic variations of the stimuli activity and DNA looping parameters. Such computation occurs in regulatory and signaling pathways in individual cells at a molecular scale, which one can exploit to design a biomolecular computer.

Can local heating and molecular crowders disintegrate amyloid aggregates?

The present study employs a blend of molecular dynamics simulations and a theoretical model to explore the potential disintegration mechanism of a matured Aß octamer, aiming to offer a strategy to combat Alzheimer's disease. We investigate local heating and crowding effects on Aß disintegration by selectively heating key Aß segments and varying the concentration of sodium dodecyl sulphate (SDS), respectively. Despite initiation of disruption, Aß aggregates resist complete disintegration during local heating due to rapid thermal energy distribution to the surrounding water. Conversely, although SDS molecules effectively inhibit Aß aggregation at higher concentration through micelle formation, they fail to completely disintegrate the aggregate due to the exceedingly high energy barrier. To address the sampling challenge posed by the formidable energy barrier, we have performed well-tempered metadynamics simulations. Simulations reveal a multi-step disintegration mechanism for the Aß octamer, suggesting a probable sequence: octamer → pentamer/hexamer ⇌ tetramer → monomer, with a rate-determining step constituting 45 kJ mol-1 barrier during the octamer to pentamer/hexamer transition. Additionally, we have proposed a novel two-state mean-field model based on Ising spins that offers an insight into the kinetics of the Aß growth process and external perturbation effects on disintegration. Thus, the current simulation study, coupled with the newly introduced mean-field model, offers an insight into the detailed mechanisms underlying the Aß aggregation process, guiding potential strategies for effective disintegration of Aß aggregates.

An Inherent Difference between Serine and Threonine Phosphorylation: Phosphothreonine Strongly Prefers a Highly Ordered, Compact, Cyclic Conformation.

Phosphorylation and dephosphorylation of proteins by kinases and phosphatases are central to cellular responses and function. The structural effects of serine and threonine phosphorylation were examined in peptides and in proteins, by circular dichroism, NMR spectroscopy, bioinformatics analysis of the PDB, small-molecule X-ray crystallography, and computational investigations. Phosphorylation of both serine and threonine residues induces substantial conformational restriction in their physiologically more important dianionic forms. Threonine exhibits a particularly strong disorder-to-order transition upon phosphorylation, with dianionic phosphothreonine preferentially adopting a cyclic conformation with restricted ϕ (ϕ ∼ -60°) stabilized by three noncovalent interactions: a strong intraresidue phosphate-amide hydrogen bond, an n → π* interaction between consecutive carbonyls, and an n → σ* interaction between the phosphate Oγ lone pair and the antibonding orbital of C-Hß that restricts the χ2 side-chain conformation. Proline is unique among the canonical amino acids for its covalent cyclization on the backbone. Phosphothreonine can mimic proline's backbone cyclization via noncovalent interactions. The preferred torsions of dianionic phosphothreonine are ϕ,ψ = polyproline II helix > α-helix (ϕ ∼ -60°); χ1 = g-; χ2 ∼ +115° (eclipsed C-H/O-P bonds). This structural signature is observed in diverse proteins, including in the activation loops of protein kinases and in protein-protein interactions. In total, these results suggest a structural basis for the differential use and evolution of threonine versus serine phosphorylation sites in proteins, with serine phosphorylation typically inducing smaller, rheostat-like changes, versus threonine phosphorylation promoting larger, step function-like switches, in proteins.

Theoretical investigation of functional responses of bio-molecular assembly networks.

Cooperative protein-protein and protein-DNA interactions form programmable complex assemblies, often performing non-linear gene regulatory operations involved in signal transductions and cell fate determination. The apparent structure of those complex assemblies is very similar, but their functional response strongly depends on the topology of the protein-DNA interaction networks. Here, we demonstrate how the coordinated self-assembly creates gene regulatory network motifs that corroborate the existence of a precise functional response at the molecular level using thermodynamic and dynamic analyses. Our theoretical and Monte Carlo simulations show that a complex network of interactions can form a decision-making loop, such as feedback and feed-forward circuits, only by a few molecular mechanisms. We characterize each possible network of interactions by systematic variations of free energy parameters associated with the binding among biomolecules and DNA looping. We also find that the higher-order networks exhibit alternative steady states from the stochastic dynamics of each network. We capture this signature by calculating stochastic potentials and attributing their multi-stability features. We validate our findings against the Gal promoter system in yeast cells. Overall, we show that the network topology is vital in phenotype diversity in regulatory circuits.

Identifying critical transitions in complex diseases.

Mortality and the burden of diseases worldwide continue to reach substantial numbers with societal development and urbanization. In the face of decline in human health, early detection of complex diseases is indispensable, albeit challenging. In this review, we document the research carried out thus far on the appearance of complex diseases marked by a critical transition or a sudden shift from a healthy state to a disease state. The theory of resilience and critical slowing down can provide practical tools to forecast the onset of various fatal and perpetuating diseases. However, critical transitions in diseases across diverse temporal and spatial scales may not always be preceded by critical slowing down. In this backdrop, an in-depth study of the underlying molecular mechanisms provides dynamic network biomarkers that can forecast potential critical transitions. We have put together the theory of complex diseases and resilience, and have discussed the need for advanced research in developing early warning signals in the field of medicine and health care. We conclude the review with a few open questions and prospects for research in this emerging field.

Combined electromechanically driven pulsating flow of nonlinear viscoelastic fluids in narrow confinements.

Controlled microscale transport is at the core of many scientific and technological advancements, including medical diagnostics, separation of biomolecules, etc., and often involves complex fluids. One of the challenges in this regard is to actuate flows at small scales in an energy efficient manner, given the strong viscous forces opposing fluid motion. We try to address this issue here by probing a combined time-periodic pressure and electrokinetically driven flow of a viscoelastic fluid obeying the simplified linear Phan-Thien-Tanner model, using numerical as well as asymptotic tools, in view of the fact that oscillatory fields are less energy intensive. We establish that the interplay between oscillatory electrical and mechanical forces can lead to complex temporal mass flow rate variations with short-term bursts and peaks in the flow rate. We further demonstrate that an oscillatory pressure gradient or an electric field, in tandem with another steady actuating force can indeed change the net throughput significantly-a paradigm that is not realized in Newtonian or other simpler polymeric liquids. Our results reveal that the extent of augmentation in the flow rate strongly depends on the frequency of the imposed actuating forces along with their waveforms. We also evaluate the streaming potential resulting from an oscillatory pressure-driven flow and illustrate that akin to the volume throughput, the streaming potential also shows complex temporal variations, while its time average gets augmented in the presence of a time-periodic pressure gradient in a nonlinear viscoelastic medium.

Anticipating response function in gene regulatory networks.

The origin of an ordered genetic response of a complex and noisy biological cell is intimately related to the detailed mechanism of protein-DNA interactions present in a wide variety of gene regulatory (GR) systems. However, the quantitative prediction of genetic response and the correlation between the mechanism and the response curve is poorly understood. Here, we report in silico binding studies of GR systems to show that the transcription factor (TF) binds to multiple DNA sites with high cooperativity spreads from specific binding sites into adjacent non-specific DNA and bends the DNA. Our analysis is not limited only to the isolated model system but also can be applied to a system containing multiple interacting genes. The controlling role of TF oligomerization, TF-ligand interactions, and DNA looping for gene expression has been also characterized. The predictions are validated against detailed grand canonical Monte Carlo simulations and published data for the lac operon system. Overall, our study reveals that the expression of target genes can be quantitatively controlled by modulating TF-ligand interactions and the bending energy of DNA.

Effects of stochasticity and social norms on complex dynamics of fisheries.

Recreational fishing is a highly socioecological process. Although recreational fisheries are self-regulating and resilient, changing anthropogenic pressure drives these fisheries to overharvest and collapse. Here, we evaluate the effect of demographic and environmental stochasticity for a social-ecological two-species fish model. In the presence of noise, we find that an increase in harvesting rate drives a critical transition from high-yield-low-price fisheries to low-yield-high-price fisheries. To calculate stochastic trajectories for demographic noise, we derive the master equation corresponding to the model and perform a Monte Carlo simulation. Moreover, the analysis of the probabilistic potential and mean first-passage time reveals the resilience of alternative steady states. We also describe the efficacy of a few generic indicators in forecasting sudden transitions. Furthermore, we show that incorporating social norms on the model allows a moderate fish density to maintain despite higher harvesting rates. Overall, our study highlights the occurrence of critical transitions in a stochastic social-ecological model and suggests ways to mitigate them.

Anticipating the Novel Coronavirus Disease (COVID-19) Pandemic.

The COVID-19 outbreak was first declared an international public health, and it was later deemed a pandemic. In most countries, the COVID-19 incidence curve rises sharply over a short period of time, suggesting a transition from a disease-free (or low-burden disease) equilibrium state to a sustained infected (or high-burden disease) state. Such a transition is often known to exhibit characteristics of "critical slowing down." Critical slowing down can be, in general, successfully detected using many statistical measures, such as variance, lag-1 autocorrelation, density ratio, and skewness. Here, we report an empirical test of this phenomena on the COVID-19 datasets of nine countries, including India, China, and the United States. For most of the datasets, increases in variance and autocorrelation predict the onset of a critical transition. Our analysis suggests two key features in predicting the COVID-19 incidence curve for a specific country: (a) the timing of strict social distancing and/or lockdown interventions implemented and (b) the fraction of a nation's population being affected by COVID-19 at that time. Furthermore, using satellite data of nitrogen dioxide as an indicator of lockdown efficacy, we found that countries where lockdown was implemented early and firmly have been successful in reducing COVID-19 spread. These results are essential for designing effective strategies to control the spread/resurgence of infectious pandemics.

Anticipating critical transitions in epithelial-hybrid-mesenchymal cell-fate determination.

In the vicinity of a tipping point, critical transitions occur when small changes in an input condition cause sudden, large, and often irreversible changes in the state of a system. Many natural systems ranging from ecosystems to molecular biosystems are known to exhibit critical transitions in their response to stochastic perturbations. In diseases, an early prediction of upcoming critical transitions from a healthy to a disease state by using early-warning signals is of prime interest due to potential application in forecasting disease onset. Here, we analyze cell-fate transitions between different phenotypes (epithelial, hybrid-epithelial/mesenchymal [E/M], and mesenchymal states) that are implicated in cancer metastasis and chemoresistance. These transitions are mediated by a mutually inhibitory feedback loop-microRNA-200/ZEB-driven by the levels of transcription factor SNAIL. We find that the proximity to tipping points enabling these transitions among different phenotypes can be captured by critical slowing down-based early-warning signals, calculated from the trajectory of ZEB messenger RNA level. Further, the basin stability analysis reveals the unexpectedly large basin of attraction for a hybrid-E/M phenotype. Finally, we identified mechanisms that can potentially elude the transition to a hybrid-E/M phenotype. Overall, our results unravel the early-warning signals that can be used to anticipate upcoming epithelial-hybrid-mesenchymal transitions. With the emerging evidence about the hybrid-E/M phenotype being a key driver of metastasis, drug resistance, and tumor relapse, our results suggest ways to potentially evade these transitions, reducing the fitness of cancer cells and restricting tumor aggressiveness.

Dynamic environment-induced multistability and critical transition in a metacommunity ecosystem.

We study a metacommunity model of consumer-resource populations coupled via dispersal under an environment-dependent framework, and we explore the occurrence of multistability and critical transition. By emphasizing two magnitudes acting on a dynamic environment at temporal and spatial scales, the coupled system with simple diffusive coupling and the nonlinear environmental coupling enables various interesting complex dynamics such as bistability, multistability, and critical transitions. Using the basin stability measure, we find the probability of attaining each alternative state in a multistable region. In addition, critical transitions (one from a high to a low species density and the other from a low to a high species density) are identified at different magnitudes in the presence of stochastic fluctuations. We also explore the robustness of critical slowing-down indicators, e.g., lag-1 autocorrelation and variance, to forewarn the critical transition in the metacommunity model. Further, a network structure also identifies synchronization and multiclustering for a different choice of initial conditions. In contrast with the earlier studies on dynamic environmental coupling, our results based on the defined magnitudes provide important insights into environmental heterogeneity, which determines the set of environmental conditions to predict metacommunity stability and persistence.

Multiview Rectification of Folded Documents.

Digitally unwrapping images of paper sheets is crucial for accurate document scanning and text recognition. This paper presents a method for automatically rectifying curved or folded paper sheets from a few images captured from multiple viewpoints. Prior methods either need expensive 3D scanners or model deformable surfaces using over-simplified parametric representations. In contrast, our method uses regular images and is based on general developable surface models that can represent a wide variety of paper deformations. Our main contribution is a new robust rectification method based on ridge-aware 3D reconstruction of a paper sheet and unwrapping the reconstructed surface using properties of developable surfaces via conformal mapping. We present results on several examples including book pages, folded letters and shopping receipts.

Size-Dependent Conformational Features of Aß17-42 Protofilaments from Molecular Simulation Studies.

Alzheimer's disease is caused due to aggregation of amyloid beta (Aß) peptide into soluble oligomers and insoluble fibrils in the brain. In this study, we have performed room temperature molecular dynamics simulations to probe the size-dependent conformational features and thermodynamic stabilities of five Aß17-42 protofilaments, namely, O5 (pentamer), O8 (octamer), O10 (decamer), O12 (dodecamer), and O14 (tetradecamer). Analysis of the free energy profiles of the aggregates showed that the higher order protofilaments (O10, O12, and O14) undergo conformational transitions between two minimum energy states separated by small energy barriers, while the smaller aggregates (O5 and O8) remain in single deep minima surrounded by high barriers. Importantly, it is demonstrated that O10 is the crossover point for which the twisting of the protofilament is maximum, beyond which the monomers tend to rearrange themselves in an intermediate state and eventually transform into more stable conformations. Our results suggest that the addition of monomers along the axis of an existing protofilament with a critical size (O10 according to the present study) proceeds via an intermediate step with relatively less stable twisted structure that allows the additional monomers to bind and form stable larger protofilaments with minor rearrangements among themselves. More importantly, it is demonstrated that a combination of twist angle and end-to-end distance can be used as a suitable reaction coordinate to describe the growth mechanism of Aß protofilaments in simulation studies.

A charge equilibration formalism for treating charge transfer effects in MD simulations: Application to water clusters.

Conventional classical force fields by construction do not explicitly partition intermolecular interactions to include polarization and charge transfer effects, whereas fully quantum mechanical treatments allow a means to effect this dissection (although not uniquely due to the lack of a charge transfer operator). Considering the importance of polarization in a variety of systems, a particular class of classical models, charge equilibration models, have been extensively developed to study those systems; since these types of interaction models are inherently based on movement of charge throughout a system, they are natural platform for including polarization and charge transfer effects within the context of molecular simulations. Here, we present two bond-space charge equilibration models we term as QE2 and mixed QE2 treat charge transfer in classical molecular mechanical calculations those provide practical solutions to two major drawbacks of charge equilibration models: (a) a nonvanishing amount of charge transfer between two heteroatoms at large separations, and (b) superlinear polarizability scaling during bond dissociation due to charge transfer over unphysical, large distances. To control charge transfer during dissociation of a bond in a molecular system, we introduce a distance-dependent scaling function (QE2 model) which, controls and recovers physical behavior of the homonuclear and heteronuclear charge transfer between two atoms at small and large values of internuclear separation; and the mixed QE2 model in which we combine the QE2 model under allow and disallow charge transfer situations that describe both charge transfer and polarizability in a distance-dependent manner. We demonstrate the utility of both models in the case of a water dimer, and compare the results with other existing models, and further, we perform short molecular dynamics simulations for few water clusters with the QE2 model to show the charge transfer and internuclear separation are correlated in dynamics. © 2017 Wiley Periodicals, Inc.

Insights into Thiol-Aromatic Interactions: A Stereoelectronic Basis for S-H/π Interactions.

Thiols can engage favorably with aromatic rings in S-H/π interactions, within abiological systems and within proteins. However, the underlying bases for S-H/π interactions are not well understood. The crystal structure of Boc-l-4-thiolphenylalanine tert-butyl ester revealed crystal organization centered on the interaction of the thiol S-H with the aromatic ring of an adjacent molecule, with a through-space Hthiol···Caromatic distance of 2.71 Å, below the 2.90 Å sum of the van der Waals radii of H and C. The nature of this interaction was further examined by DFT calculations, IR spectroscopy, solid-state NMR spectroscopy, and analysis of the Cambridge Structural Database. The S-H/π interaction was found to be driven significantly by favorable molecular orbital interactions, between an aromatic π donor orbital and the S-H σ* acceptor orbital (a π → σ* interaction). For comparison, a structural analysis of O-H/π interactions and of cation/π interactions of alkali metal cations with aromatic rings was conducted. Na+ and K+ exhibit a significant preference for the centroid of the aromatic ring and distances near the sum of the van der Waals and ionic radii, as expected for predominantly electrostatic interactions. Li+ deviates substantially from Na+ and K+. The S-H/π interaction differs from classical cation/π interactions by the preferential alignment of the S-H σ* toward the ring carbons and an aromatic π orbital rather than toward the aromatic centroid. These results describe a potentially broadly applicable approach to understanding the interactions of weakly polar bonds with π systems.

Robust Multiview Photometric Stereo Using Planar Mesh Parameterization.

We propose a robust uncalibrated multiview photometric stereo method for high quality 3D shape reconstruction. In our method, a coarse initial 3D mesh obtained using a multiview stereo method is projected onto a 2D planar domain using a planar mesh parameterization technique. We describe methods for surface normal estimation that work in the parameterized 2D space that jointly incorporates all geometric and photometric cues from multiple viewpoints. Using an estimated surface normal map, a refined 3D mesh is then recovered by computing an optimal displacement map in the same 2D planar domain. Our method avoids the need of merging view-dependent surface normal maps that is often required in conventional methods. We conduct evaluation on various real-world objects containing surfaces with specular reflections, multiple albedos, and complex topologies in both controlled and uncontrolled settings and demonstrate that accurate 3D meshes with fine geometric details can be recovered by our method.

Thermodynamics of complex structures formed between single-stranded DNA oligomers and the KH domains of the far upstream element binding protein.

The noncovalent interaction between protein and DNA is responsible for regulating the genetic activities in living organisms. The most critical issue in this problem is to understand the underlying driving force for the formation and stability of the complex. To address this issue, we have performed atomistic molecular dynamics simulations of two DNA binding K homology (KH) domains (KH3 and KH4) of the far upstream element binding protein (FBP) complexed with two single-stranded DNA (ss-DNA) oligomers in aqueous media. Attempts have been made to calculate the individual components of the net entropy change for the complexation process by adopting suitable statistical mechanical approaches. Our calculations reveal that translational, rotational, and configurational entropy changes of the protein and the DNA components have unfavourable contributions for this protein-DNA association process and such entropy lost is compensated by the entropy gained due to the release of hydration layer water molecules. The free energy change corresponding to the association process has also been calculated using the Free Energy Perturbation (FEP) method. The free energy gain associated with the KH4-DNA complex formation has been found to be noticeably higher than that involving the formation of the KH3-DNA complex.

Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics.

Cell-penetrating and antimicrobial peptides show a remarkable ability to translocate across physiological membranes. Along with factors such as electric-potential-induced perturbations of membrane structure and surface tension effects, experiments invoke porelike membrane configurations during the solute transfer process into vesicles and cells. The initiation and formation of pores are associated with a nontrivial free-energy cost, thus necessitating a consideration of the factors associated with pore formation and the attendant free energies. Because of experimental and modeling challenges related to the long time scales of the translocation process, we use umbrella sampling molecular dynamics simulations with a lipid-density-based order parameter to investigate membrane-pore-formation free energy employing Martini coarse-grained models. We investigate structure and thermodynamic features of the pore in 18 lipids spanning a range of headgroups, charge states, acyl chain lengths, and saturation. We probe the dependence of pore-formation barriers on the area per lipid, lipid bilayer thickness, and membrane bending rigidities in three different lipid classes. The pore-formation free energy in pure bilayers and peptide translocating scenarios are significantly coupled with bilayer thickness. Thicker bilayers require more reversible work to create pores. The pore-formation free energy is higher in peptide-lipid systems than in peptide-free lipid systems due to penalties to maintain the solvation of charged hydrophilic solutes within the membrane environment.

In silico studies of the properties of water hydrating a small protein.

Atomistic molecular dynamics simulation of an aqueous solution of the small protein HP-36 has been carried out with explicit solvent at room temperature. Efforts have been made to explore the influence of the protein on the relative packing and ordering of water molecules around its secondary structures, namely, three α-helices. The calculations reveal that the inhomogeneous water ordering and density distributions around the helices are correlated with their relative hydrophobicity. Importantly, we have identified the existence of a narrow relatively dehydrated region containing randomly organized "quasi-free" water molecules beyond the first layer of "bound" waters at the protein surface. These water molecules with relatively weaker binding energies form the transition state separating the "bound" and "free" water molecules at the interface. Further, increased contribution of solid-like caging motions of water molecules around the protein is found to be responsible for reduced fluidity of the hydration layer. Interestingly, we notice that the hydration layer of helix-3 is more fluidic with relatively higher entropy as compared to the hydration layers of the other two helical segments. Such characteristics of helix-3 hydration layer correlate well with the activity of HP-36, as helix-3 contains the active site of the protein.

Reconciling structural and thermodynamic predictions using all-atom and coarse-grain force fields: the case of charged oligo-arginine translocation into DMPC bilayers.

Using the translocation of short, charged cationic oligo-arginine peptides (mono-, di-, and triarginine) from bulk aqueous solution into model DMPC bilayers, we explore the question of the similarity of thermodynamic and structural predictions obtained from molecular dynamics simulations using all-atom and Martini coarse-grain force fields. Specifically, we estimate potentials of mean force associated with translocation using standard all-atom (CHARMM36 lipid) and polarizable and nonpolarizable Martini force fields, as well as a series of modified Martini-based parameter sets. We find that we are able to reproduce qualitative features of potentials of mean force of single amino acid side chain analogues into model bilayers. In particular, modifications of peptide-water and peptide-membrane interactions allow prediction of free energy minima at the bilayer-water interface as obtained with all-atom force fields. In the case of oligo-arginine peptides, the modified parameter sets predict interfacial free energy minima as well as free energy barriers in almost quantitative agreement with all-atom force field based simulations. Interfacial free energy minima predicted by a modified coarse-grained parameter set are -2.51, -4.28, and -5.42 for mono-, di-, and triarginine; corresponding values from all-atom simulations are -0.83, -3.33, and -3.29, respectively, all in units of kcal/mol. We found that a stronger interaction between oligo-arginine and the membrane components and a weaker interaction between oligo-arginine and water are crucial for producing such minima in PMFs using the polarizable CG model. The difference between bulk aqueous and bilayer center states predicted by the modified coarse-grain force field are 11.71, 14.14, and 16.53 kcal/mol, and those by the all-atom model are 6.94, 8.64, and 12.80 kcal/mol; those are of almost the same order of magnitude. Our simulations also demonstrate a remarkable similarity in the structural aspects of the ensemble of configurations generated using the all-atom and coarse-grain force fields. Both resolutions show that oligo-arginine peptides adopt preferential orientations as they translocate into the bilayer. The guiding theme centers on charged groups maintaining coordination with polar and charged bilayer components as well as local water. We also observe similar behaviors related with membrane deformations.