Modeling the Role of Immune Cell Conversion in the Tumor-Immune Microenvironment.

Tumors develop in a complex physical, biochemical, and cellular milieu, referred to as the tumor microenvironment. Of special interest is the set of immune cells that reciprocally interact with the tumor, the tumor-immune microenvironment (TIME). The diversity of cell types and cell-cell interactions in the TIME has led researchers to apply concepts from ecology to describe the dynamics.

Permissive and nonpermissive channel closings in CFTR revealed by a factor graph inference algorithm.

The closing of the gated ion channel in the cystic fibrosis transmembrane conductance regulator can be categorized as nonpermissive to reopening, which involves the unbinding of ADP or ATP, or permissive, which does not. Identifying the type of closing is of interest as interactions with nucleotides can be affected in mutants or by introducing agonists. However, all closings are electrically silent and difficult to differentiate.

Cheater suppression and stochastic clearance through quorum sensing.

The evolutionary consequences of quorum sensing in regulating bacterial cooperation are not fully understood. In this study, we reveal unexpected effects of regulating public good production through quorum sensing on bacterial population dynamics, showing that quorum sensing can be a collectively harmful alternative to unregulated production. We analyze a birth-death model of bacterial population dynamics accounting for public good production and the presence of non-producing cheaters.

Minimal informational requirements for fitness.

The existing concept of the "fitness value of information" provides a theoretical upper bound on the fitness advantage of using information concerning a fluctuating environment. Using concepts from rate-distortion theory, we develop a theoretical framework to answer a different pair of questions: What is the minimal amount of information needed for a population to achieve a certain growth rate? What is the minimal amount of information gain needed for one subpopulation to achieve a certain average selection coefficient over another? We introduce a correspondence between fitness and distortion and solve for the rate-distortion functions of several systems using analytical and numerical methods. Because accurate information processing is energetically costly, our approach provides a theoretical basis for understanding evolutionary "design principles" underlying information-cost trade-offs.

Fitness value of information with delayed phenotype switching: Optimal performance with imperfect sensing.

The ability of organisms to accurately sense their environment and respond accordingly is critical for evolutionary success. However, exactly how the sensory ability influences fitness is a topic of active research, while the necessity of a time delay between when unreliable environmental cues are sensed and when organisms can mount a response has yet to be explored at any length. Accounting for this delay in phenotype response in models of population growth, we find that a critical error probability can exist under certain environmental conditions: An organism with a sensory system with any error probability less than the critical value can achieve the same long-term growth rate as an organism with a perfect sensing system.

Structural Consequences of Multisite Phosphorylation in the BAK1 Kinase Domain.

Multisite phosphorylation is an important mechanism of post-translational control of protein kinases. The effects of combinations of possible phosphorylation states on protein kinase activity are difficult to study experimentally because of challenges in isolating a particular phosphorylation state; surprising little effort on this topic has been expended in computational studies. To understand the effects of multisite phosphorylation on the plant protein kinase brassinosteroid insensitive 1-associated kinase 1 (BAK1) conformational ensemble, we performed Gaussian accelerated molecular dynamics simulations on eight BAK1 mod-forms involving phosphorylation of the four activation-loop threonine residues and binding of ATP-Mg.

Molecular Mechanism of Brassinosteroid Perception by the Plant Growth Receptor BRI1.

Brassinosteroids (BRs) are essential phytohormones, which bind to the plant receptor, BRI1, to regulate various physiological processes. The molecular mechanism of the perception of BRs by the ectodomain of BRI1 remains not fully understood. It also remains elusive why a substantial difference in biological activity exists between the BRs.

Using molecular simulation to explore the nanoscale dynamics of the plant kinome.

Eukaryotic protein kinases (PKs) are a large family of proteins critical for cellular response to external signals, acting as molecular switches. PKs propagate biochemical signals by catalyzing phosphorylation of other proteins, including other PKs, which can undergo conformational changes upon phosphorylation and catalyze further phosphorylations. Although PKs have been studied thoroughly across the domains of life, the structures of these proteins are sparsely understood in numerous groups of organisms, including plants.

Publisher Correction: Enhanced unbiased sampling of protein dynamics using evolutionary coupling information.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Allosteric Control of a Plant Receptor Kinase through S-Glutathionylation.

Growing evidence supports the importance of protein S-glutathionylation as a regulatory post-translational modification with functional consequences for proteins. Discoveries of redox-state-dependent protein kinase S-glutathionylation have fueled discussion of redox-sensitive signaling. Following previously published experimental evidence for S-glutathionylation induced deactivation of the Arabidopsis thaliana kinase BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED RECEPTOR-LIKE KINASE 1 (BAK1), we investigated the consequences of S-glutathionylation on the equilibrium conformational ensemble of BAK1 using all-atom molecular dynamics simulations.

Enhanced unbiased sampling of protein dynamics using evolutionary coupling information.

One of the major challenges in atomistic simulations of proteins is efficient sampling of pathways associated with rare conformational transitions. Recent developments in statistical methods for computation of direct evolutionary couplings between amino acids within and across polypeptide chains have allowed for inference of native residue contacts, informing accurate prediction of protein folds and multimeric structures. In this study, we assess the use of distances between evolutionarily coupled residues as natural choices for reaction coordinates which can be incorporated into Markov state model-based adaptive sampling schemes and potentially used to predict not only functional conformations but also pathways of conformational change, protein folding, and protein-protein association.

Molecular dynamics simulations reveal the conformational dynamics of BRI1 and BAK1 receptor-like kinases.

The structural motifs responsible for activation and regulation of eukaryotic protein kinases in animals have been studied extensively in recent years, and a coherent picture of their activation mechanisms has begun to emerge. In contrast, non-animal eukaryotic protein kinases are not as well understood from a structural perspective, representing a large knowledge gap. To this end, we investigated the conformational dynamics of two key receptor-like kinases, brassinosteroid-insensitive 1 (BRI1) and BRI1-associated kinase 1 (BAK1), through extensive molecular dynamics simulations of their fully phosphorylated kinase domains.

Application of Hidden Markov Models in Biomolecular Simulations.

Hidden Markov models (HMMs) provide a framework to analyze large trajectories of biomolecular simulation datasets. HMMs decompose the conformational space of a biological molecule into finite number of states that interconvert among each other with certain rates. HMMs simplify long timescale trajectories for human comprehension, and allow comparison of simulations with experimental data.