How insulin binds to its receptor is unknown despite decades of investigation. Here, we employ chiral mutagenesis-comparison of corresponding D and L amino acid substitutions in the hormoneto define a structural switch between folding-competent and active conformations. Our strategy is motivated by the T R transition, an allosteric feature of zinc-hexamer assembly in which an invariant glycine in the B chain changes conformations. In the classical T state, Gly B8 lies within a -turn and exhibits a positive ϕ angle (like a D amino acid); in the alternative R state, Gly B8 is part of an -helix and exhibits a negative ϕ angle (like an L amino acid). Respective B chain libraries containing mixtures of D or L substitutions at B8 exhibit a stereospecific perturbation of insulin chain combination: L amino acids impede native disulfide pairing, whereas diverse D substitutions are well-tolerated. Strikingly, D substitutions at B8 enhance both synthetic yield and thermodynamic stability but markedly impair biological activity. The NMR structure of such an inactive analogue (as an engineered T-like monomer) is essentially identical to that of native insulin. By contrast, L analogues exhibit impaired folding and stability. Although synthetic yields are very low, such analogues can be highly active. Despite the profound differences between the foldabilities of D and L analogues, crystallization trials suggest that on protein assembly substitutions of either class can be accommodated within classical T or R states. Comparison between such diastereomeric analogues thus implies that the T state represents an inactive but folding-competent conformation. We propose that within folding intermediates the sign of the B8 ϕ angle exerts kinetic control in a rugged landscape to distinguish between trajectories associated † This work was supported in part by Diabetes Research and Training Center at the University of Chicago (S. H SUPPORTING INFORMATION AVAILABLENine figures illustrating disulfide pairing and structural relationships in insulin crystals, visible absorption spectra of cobalt-substituted hexamers, additional CD and NMR spectra, diagonal plot of NOEs, and summary of NMR sequential assignment. Nine tables providing B8 dihedral angles, summary of mutations at sites neighboring B8, crystallographic unit-cell dimensions, NMR resonance assignments, statistical information pertaining to DG/RMD ensemble, and restraints. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2013 December 02. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript with productive disulfide pairing (positive T-like values) or off-pathway events (negative R-like values). We further propose that the crystallographic T R transition in part recapitulates how the conformation of an insulin monomer changes on receptor binding. At the very least the ostensibly unrelated processes of disulfide pairing, allosteric assemb...
We design simple mechanisms to approximate the Gains from Trade (GFT) in two-sided markets with multiple unit-supply sellers and multiple unit-demand buyers. A classical impossibility result by Myerson and Satterthwaite [22] showed that even with only one seller and one buyer, no Individually Rational (IR), Bayesian Incentive Compatible (BIC) and Budget-Balanced (BB) mechanism can achieve full GFT (trade whenever buyer's value is higher than the seller's cost). On the other hand, they proposed the "second-best" mechanism that maximizes the GFT subject to IR, BIC and BB constraints, which is unfortunately rather complex for even the single-seller single-buyer case. Our mechanism is simple, IR, BIC and BB, and achieves 1 2 of the optimal GFT among all IR, BIC and BB mechanisms. Our result holds for arbitrary distributions of the buyers' and sellers' values and can accommodate any downward-closed feasibility constraints over the allocations. The analysis of our mechanism is facilitated by extending the Cai-Weinberg-Devanur duality framework [4] to two-sided markets.
In this paper, we address the important issue of uncertainty in the edge influence probability estimates for the well studied influence maximization problem -the task of finding k seed nodes in a social network to maximize the influence spread. We propose the problem of robust influence maximization, which maximizes the worst-case ratio between the influence spread of the chosen seed set and the optimal seed set, given the uncertainty of the parameter input. We design an algorithm that solves this problem with a solutiondependent bound. We further study uniform sampling and adaptive sampling methods to effectively reduce the uncertainty on parameters and improve the robustness of the influence maximization task. Our empirical results show that parameter uncertainty may greatly affect influence maximization performance and prior studies that learned influence probabilities could lead to poor performance in robust influence maximization due to relatively large uncertainty in parameter estimates, and information cascade based adaptive sampling method may be an effective way to improve the robustness of influence maximization.
We provide simple and approximately revenue-optimal mechanisms in the multi-item multi-bidder settings. We unify and improve all previous results, as well as generalize the results to broader cases. In particular, we prove that the better of the following two simple, deterministic and Dominant Strategy Incentive Compatible mechanisms, a sequential posted price mechanism or an anonymous sequential posted price mechanism with entry fee, achieves a constant fraction of the optimal revenue among all randomized, Bayesian Incentive Compatible mechanisms, when buyers' valuations are XOS over independent items. If the buyers' valuations are subadditive over independent items, the approximation factor degrades to O(log m), where m is the number of items. We obtain our results by first extending the Cai-Devanur-Weinberg duality framework to derive an effective benchmark of the optimal revenue for subadditive bidders, and then analyzing this upper bound with new techniques.
Peptoids (poly-N-substituted glycines) are a class of synthetic polymers that are regioisomers of peptides (poly-C-substituted glycines), in which the point of side-chain connectivity is shifted from the backbone C to the N atom. Peptoids have found diverse applications as peptidomimetic drugs, protein mimetic polymers, surfactants, and catalysts. Computational modeling is valuable in the understanding and design of peptoid-based nanomaterials. In this work, we report the bottom-up parameterization of coarse-grained peptoid force fields based on the MARTINI peptide force field against all-atom peptoid simulation data. Our parameterization pipeline iteratively refits coarse-grained bonded interactions using iterative Boltzmann inversion and nonbonded interactions by matching the potential of mean force for chain extension. We assure good sampling of the amide bond cis/trans isomerizations in the all-atom simulation data using parallel bias metadynamics. We develop coarse-grained models for two representative peptoidspolysarcosine (poly(N-methyl glycine)) and poly(N-((4-bromophenyl)ethyl)glycine)and show their structural and thermodynamic properties to be in excellent accord with all-atom calculations but up to 25-fold more efficient and compatible with MARTINI force fields. This work establishes a new rigorously parameterized coarse-grained peptoid force field for the understanding and design of peptoid nanomaterials at length and time scales inaccessible to all-atom calculations.
Maturity-onset diabetes of the young, a monogenic form of Type II diabetes mellitus, is most commonly caused by mutations in hepatic nuclear factor 1α (HNF-1α). Here, the dimerization motif of HNF-1α is shown to form an intermolecular four-helix bundle. One face contains an antiparallel coiled coil whereas the other contains splayed α-helices. The “mini-zipper” is complementary in structure and symmetry to the top surface of a transcriptional coactivator (dimerization cofactor of homeodomains). The bundle is destabilized by a subset of mutations associated with maturity-onset diabetes of the young. Impaired dimerization of a β-cell transcription factor thus provides a molecular mechanism of metabolic deregulation in diabetes mellitus.
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