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NCBI: db=pubmed; Term=(Im, Wonpil[Author] AND Kansas) OR (Vakser, Ilya[Author]) OR (Karanicolas, John[Author] AND Kansas) OR (Deeds, Eric[Author]) OR (Ray, Christian[Author]) OR (Slusky, Joanna[Author]) OR (Ray JC[Author] AND Kansas)
Updated: 8 hours 28 min ago

Fundamental trade-offs between information flow in single cells and cellular populations.

Sun, 05/14/2017 - 10:12
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Fundamental trade-offs between information flow in single cells and cellular populations.

Proc Natl Acad Sci U S A. 2017 May 12;:

Authors: Suderman R, Bachman JA, Smith A, Sorger PK, Deeds EJ

Abstract
Signal transduction networks allow eukaryotic cells to make decisions based on information about intracellular state and the environment. Biochemical noise significantly diminishes the fidelity of signaling: networks examined to date seem to transmit less than 1 bit of information. It is unclear how networks that control critical cell-fate decisions (e.g., cell division and apoptosis) can function with such low levels of information transfer. Here, we use theory, experiments, and numerical analysis to demonstrate an inherent trade-off between the information transferred in individual cells and the information available to control population-level responses. Noise in receptor-mediated apoptosis reduces information transfer to approximately 1 bit at the single-cell level but allows 3-4 bits of information to be transmitted at the population level. For processes such as eukaryotic chemotaxis, in which single cells are the functional unit, we find high levels of information transmission at a single-cell level. Thus, low levels of information transfer are unlikely to represent a physical limit. Instead, we propose that signaling networks exploit noise at the single-cell level to increase population-level information transfer, allowing extracellular ligands, whose levels are also subject to noise, to incrementally regulate phenotypic changes. This is particularly critical for discrete changes in fate (e.g., life vs. death) for which the key variable is the fraction of cells engaged. Our findings provide a framework for rationalizing the high levels of noise in metazoan signaling networks and have implications for the development of drugs that target these networks in the treatment of cancer and other diseases.

PMID: 28500273 [PubMed - as supplied by publisher]

Computational screening and design for compounds that disrupt protein-protein interactions.

Wed, 05/10/2017 - 08:12
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Computational screening and design for compounds that disrupt protein-protein interactions.

Curr Top Med Chem. 2017 May 08;:

Authors: Johnson DK, Karanicolas J

Abstract
Protein-protein interactions play key roles in all biological processes, motivating numerous campaigns to seek small-molecule disruptors of therapeutically relevant interactions. Two decades ago, the prospect of developing small-molecule inhibitors was thought to be perhaps impossible due to the potentially undruggable nature of the protein surfaces involved; this viewpoint was reinforced by the limited successes provided from traditional high-throughput screens. To date, however, refinement of new experimental approaches has led to a multitude of inhibitors against many different targets. Having thus established the feasibility of attaining success in this valuable and diverse target space, attention now turns to incorporating computational techniques that might assist during various stages of drug design and optimization. Here we review cases in which computational approaches - virtual screening, docking, and ligand optimization - have contributed to discovery of new inhibitors of protein-protein interactions. We conclude by providing an outlook into the upcoming challenges and recent advances likely to shape this field moving forward.

PMID: 28482793 [PubMed - as supplied by publisher]

Chaperonin-Based Biolayer Interferometry To Assess the Kinetic Stability of Metastable, Aggregation-Prone Proteins.

Wed, 05/10/2017 - 08:12
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Chaperonin-Based Biolayer Interferometry To Assess the Kinetic Stability of Metastable, Aggregation-Prone Proteins.

Biochemistry. 2016 Sep 06;55(35):4885-908

Authors: Lea WA, O'Neil PT, Machen AJ, Naik S, Chaudhri T, McGinn-Straub W, Tischer A, Auton MT, Burns JR, Baldwin MR, Khar KR, Karanicolas J, Fisher MT

Abstract
Stabilizing the folded state of metastable and/or aggregation-prone proteins through exogenous ligand binding is an appealing strategy for decreasing disease pathologies caused by protein folding defects or deleterious kinetic transitions. Current methods of examining binding of a ligand to these marginally stable native states are limited because protein aggregation typically interferes with analysis. Here, we describe a rapid method for assessing the kinetic stability of folded proteins and monitoring the effects of ligand stabilization for both intrinsically stable proteins (monomers, oligomers, and multidomain proteins) and metastable proteins (e.g., low Tm) that uses a new GroEL chaperonin-based biolayer interferometry (BLI) denaturant pulse platform. A kinetically controlled denaturation isotherm is generated by exposing a target protein, immobilized on a BLI biosensor, to increasing denaturant concentrations (urea or GuHCl) in a pulsatile manner to induce partial or complete unfolding of the attached protein population. Following the rapid removal of the denaturant, the extent of hydrophobic unfolded/partially folded species that remains is detected by an increased level of GroEL binding. Because this kinetic denaturant pulse is brief, the amplitude of binding of GroEL to the immobilized protein depends on the duration of the exposure to the denaturant, the concentration of the denaturant, wash times, and the underlying protein unfolding-refolding kinetics; fixing all other parameters and plotting the GroEL binding amplitude versus denaturant pulse concentration result in a kinetically controlled denaturation isotherm. When folding osmolytes or stabilizing ligands are added to the immobilized target proteins before and during the denaturant pulse, the diminished population of unfolded/partially folded protein manifests as a decreased level of GroEL binding and/or a marked shift in these kinetically controlled denaturation profiles to higher denaturant concentrations. This particular platform approach can be used to identify small molecules and/or solution conditions that can stabilize or destabilize thermally stable proteins, multidomain proteins, oligomeric proteins, and, most importantly, aggregation-prone metastable proteins.

PMID: 27505032 [PubMed - indexed for MEDLINE]

Replacing Arginine 33 for Alanine in the Hemophore HasA from Pseudomonas aeruginosa Causes Closure of the H32 Loop in the Apo-Protein.

Sun, 04/30/2017 - 16:03
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Replacing Arginine 33 for Alanine in the Hemophore HasA from Pseudomonas aeruginosa Causes Closure of the H32 Loop in the Apo-Protein.

Biochemistry. 2016 May 10;55(18):2622-31

Authors: Kumar R, Qi Y, Matsumura H, Lovell S, Yao H, Battaile KP, Im W, Moënne-Loccoz P, Rivera M

Abstract
Previous characterization of hemophores from Serratia marcescens (HasAs), Pseudomonas aeruginosa (HasAp), and Yersinia pestis (HasAyp) showed that hemin binds between two loops, where it is axially coordinated by H32 and Y75. The Y75 loop is structurally conserved in all three hemophores and harbors conserved ligand Y75. The other loop contains H32 in HasAs and HasAp, but a noncoordinating Q32 in HasAyp. The H32 loop in apo-HasAs and apo-HasAp is in an open conformation, which places H32 about 30 Å from the hemin-binding site. Hence, hemin binding onto the Y75 loop of HasAs or HasAp triggers a large relocation of the H32 loop from an open- to a closed-loop conformation and enables coordination of the hemin-iron by H32. In comparison, the Q32 loop in apo-HasAyp is in the closed conformation, and hemin binding occurs with minimal reorganization and without coordinative interactions with the Q32 loop. Studies in crystallo and in solution have established that the open H32 loop in apo-HasAp and apo-HasAs is well structured and minimally affected by conformational dynamics. In this study we address the intriguing issue of the stability of the H32 loop in apo-HasAp and how hemin binding triggers its relocation. We address this question with a combination of NMR spectroscopy, X-ray crystallography, and molecular dynamics simulations and find that R33 is critical to the stability of the open H32 loop. Replacing R33 with A causes the H32 loop in R33A apo-HasAp to adopt a conformation similar to that of holo-HasAp. Finally, stopped-flow absorption and resonance Raman analyses of hemin binding to apo-R33A HasAp indicate that the closed H32 loop slows down the insertion of the heme inside the binding pocket, presumably as it obstructs access to the hydrophobic platform on the Y75 loop, but accelerates the completion of the heme iron coordination.

PMID: 27074415 [PubMed - indexed for MEDLINE]

The fungal natural product azaphilone-9 binds to HuR and inhibits HuR-RNA interaction in vitro.

Tue, 04/18/2017 - 09:07
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The fungal natural product azaphilone-9 binds to HuR and inhibits HuR-RNA interaction in vitro.

PLoS One. 2017;12(4):e0175471

Authors: Kaur K, Wu X, Fields JK, Johnson DK, Lan L, Pratt M, Somoza AD, Wang CCC, Karanicolas J, Oakley BR, Xu L, De Guzman RN

Abstract
The RNA-binding protein Hu antigen R (HuR) binds to AU-rich elements (ARE) in the 3'-untranslated region (UTR) of target mRNAs. The HuR-ARE interactions stabilize many oncogenic mRNAs that play important roles in tumorigenesis. Thus, small molecules that interfere with the HuR-ARE interaction could potentially inhibit cancer cell growth and progression. Using a fluorescence polarization (FP) competition assay, we identified the compound azaphilone-9 (AZA-9) derived from the fungal natural product asperbenzaldehyde, binds to HuR and inhibits HuR-ARE interaction (IC50 ~1.2 μM). Results from surface plasmon resonance (SPR) verified the direct binding of AZA-9 to HuR. NMR methods mapped the RNA-binding interface of HuR and identified the involvement of critical RNA-binding residues in binding of AZA-9. Computational docking was then used to propose a likely binding site for AZA-9 in the RNA-binding cleft of HuR. Our results show that AZA-9 blocks key RNA-binding residues of HuR and disrupts HuR-RNA interactions in vitro. This knowledge is needed in developing more potent AZA-9 derivatives that could lead to new cancer therapy.

PMID: 28414767 [PubMed - in process]

Gramicidin A Channel Formation Induces Local Lipid Redistribution II: A 3D Continuum Elastic Model.

Thu, 03/30/2017 - 11:09
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Gramicidin A Channel Formation Induces Local Lipid Redistribution II: A 3D Continuum Elastic Model.

Biophys J. 2017 Mar 28;112(6):1198-1213

Authors: Sodt AJ, Beaven AH, Andersen OS, Im W, Pastor RW

Abstract
To change conformation, a protein must deform the surrounding bilayer. In this work, a three-dimensional continuum elastic model for gramicidin A in a lipid bilayer is shown to describe the sensitivity to thickness, curvature stress, and the mechanical properties of the lipid bilayer. A method is demonstrated to extract the gramicidin-lipid boundary condition from all-atom simulations that can be used in the three-dimensional continuum model. The boundary condition affects the deformation dramatically, potentially much more than typical variations in the material stiffness do as lipid composition is changed. Moreover, it directly controls the sensitivity to curvature stress. The curvature stress and hydrophobic surfaces of the all-atom and continuum models are found to be in excellent agreement. The continuum model is applied to estimate the enrichment of hydrophobically matched lipids near the channel in a mixture, and the results agree with single-channel experiments and extended molecular dynamics simulations from the companion article by Beaven et al. in this issue of Biophysical Journal.

PMID: 28355547 [PubMed - in process]

Gramicidin A Channel Formation Induces Local Lipid Redistribution I: Experiment and Simulation.

Thu, 03/30/2017 - 11:09
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Gramicidin A Channel Formation Induces Local Lipid Redistribution I: Experiment and Simulation.

Biophys J. 2017 Mar 28;112(6):1185-1197

Authors: Beaven AH, Maer AM, Sodt AJ, Rui H, Pastor RW, Andersen OS, Im W

Abstract
Integral membrane protein function can be modulated by the host bilayer. Because biological membranes are diverse and nonuniform, we explore the consequences of lipid diversity using gramicidin A channels embedded in phosphatidylcholine (PC) bilayers composed of equimolar mixtures of di-oleoyl-PC and di-erucoyl-PC (dC18:1+dC22:1, respectively), di-palmitoleoyl-PC and di-nervonoyl-PC (dC16:1+dC24:1, respectively), and di-eicosenoyl-PC (pure dC20:1), all of which have the same average bilayer chain length. Single-channel lifetime experiments, molecular dynamics simulations, and a simple lipid compression model are used in tandem to gain insight into lipid redistribution around the channel, which partially alleviates the bilayer deformation energy associated with channel formation. The average single-channel lifetimes in the two-component bilayers (95 ± 10 ms for dC18:1+dC22:1 and 195 ± 20 ms for dC16:1+dC24:1) were increased relative to the single-component dC20:1 control bilayer (65 ± 10 ms), implying lipid redistribution. Using a theoretical treatment of thickness-dependent changes in channel lifetimes, the effective local enrichment of lipids around the channel was estimated to be 58 ± 4% dC18:1 and 66 ± 2% dC16:1 in the dC18:1+dC22:1 and dC16:1+dC24:1 bilayers, respectively. 3.5-μs molecular dynamics simulations show 66 ± 2% dC16:1 in the first lipid shell around the channel in the dC16:1+dC24:1 bilayer, but no significant redistribution (50 ± 4% dC18:1) in the dC18:1+dC22:1 bilayer; these simulated values are within the 95% confidence intervals of the experimental averages. The strong preference for the better matching lipid (dC16:1) near the channel in the dC16:1+dC24:1 mixture and lesser redistribution in the dC18:1+dC22:1 mixture can be explained by the energetic cost associated with compressing the lipids to match the channel's hydrophobic length.

PMID: 28355546 [PubMed - in process]

"Solvent hydrogen-bond occlusion": A new model of polar desolvation for biomolecular energetics.

Tue, 03/21/2017 - 06:10

"Solvent hydrogen-bond occlusion": A new model of polar desolvation for biomolecular energetics.

J Comput Chem. 2017 Mar 20;:

Authors: Bazzoli A, Karanicolas J

Abstract
Water engages in two important types of interactions near biomolecules: it forms ordered "cages" around exposed hydrophobic regions, and it participates in hydrogen bonds with surface polar groups. Both types of interaction are critical to biomolecular structure and function, but explicitly including an appropriate number of solvent molecules makes many applications computationally intractable. A number of implicit solvent models have been developed to address this problem, many of which treat these two solvation effects separately. Here, we describe a new model to capture polar solvation effects, called SHO ("solvent hydrogen-bond occlusion"); our model aims to directly evaluate the energetic penalty associated with displacing discrete first-shell water molecules near each solute polar group. We have incorporated SHO into the Rosetta energy function, and find that scoring protein structures with SHO provides superior performance in loop modeling, virtual screening, and protein structure prediction benchmarks. These improvements stem from the fact that SHO accurately identifies and penalizes polar groups that do not participate in hydrogen bonds, either with solvent or with other solute atoms ("unsatisfied" polar groups). We expect that in future, SHO will enable higher-resolution predictions for a variety of molecular modeling applications. © 2017 Wiley Periodicals, Inc.

PMID: 28318014 [PubMed - as supplied by publisher]

Survival of Phenotypic Information during Cellular Growth Transitions.

Sat, 03/04/2017 - 09:04
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Survival of Phenotypic Information during Cellular Growth Transitions.

ACS Synth Biol. 2016 08 19;5(8):810-6

Authors: Ray JC

Abstract
Phenotypic memory can predispose cells to physiological outcomes, contribute to heterogeneity in cellular populations, and allow computation of environmental features, such as nutrient gradients. In bacteria and synthetic circuits in general, memory can often be set by protein concentrations: because of the relative stability of proteins, the degradation rate is often dominated by the growth rate, and inheritance is a significant factor. Cells can then be primed to respond to events that recur with frequencies faster than the time to eliminate proteins. Protein memory can be extended if cells reach extremely low growth rates or no growth. Here we characterize the necessary time scales for different quantities of protein memory, measured as relative entropy (Kullback-Leibler divergence), for a variety of cellular growth arrest transition dynamics. We identify a critical manifold in relative protein degradation/growth arrest time scales where information is, in principle, preserved indefinitely because proteins are trapped at a concentration determined by the competing time scales as long as nongrowth-mediated protein degradation is negligible. We next asked what characteristics of growth arrest dynamics and initial protein distributions best preserve or eliminate information about previous environments. We identified that sharp growth arrest transitions with skewed initial protein distributions optimize flexibility, with information preservation and minimal cost of residual protein. As a result, a nearly memoryless regime, corresponding to a form of bet-hedging, may be an optimal strategy for storage of information by protein concentrations in growth-arrested cells.

PMID: 26910476 [PubMed - indexed for MEDLINE]


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