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Ligand-receptor interaction catalyzes the aggregation of small molecules to induce cell necroptosis.

ABSTRACT: Because they exhibit important biological functions, from unfolding proteins to activating enzymes to controlling cell fates, aggregates of small molecules are able to serve as functional molecular entities in cellular environments. However, the inability to precisely control their production has hampered the understanding and exploration of their biological functions. Here we show that the well-established ligand-receptor interaction between vancomycin and d-Ala-d-Ala catalyzes the aggregation of a d-Ala-d-Ala-containing small peptide derivative in water. The resulting aggregates largely adhere to the cell surface to induce cell necroptosis. Mutation of d-Ala-d-Ala to l-Ala-l-Ala or removal of the aromatic group in the derivative results in innocuous compounds, confirming that the aromatic-aromatic and ligand-receptor interactions are responsible for the formation and corresponding cytotoxicity of the aggregates. In addition to being the first example of ligand-receptor interaction-catalyzed aggregation of small molecules on the surface of mammalian cells, this work provides useful insights for understanding the cytotoxicity of molecular aggregates of small molecules.

SUBMITTER: Shi J

PROVIDER: S-EPMC4295010 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Ligand-receptor interaction catalyzes the aggregation of small molecules to induce cell necroptosis.

Shi Junfeng J Du Xuewen X Huang Yibing Y Zhou Jie J Yuan Dan D Wu Dongdong D Zhang Ye Y Haburcak Richard R Epstein Irving R IR Xu Bing B

Journal of the American Chemical Society 20141226 1

Because they exhibit important biological functions, from unfolding proteins to activating enzymes to controlling cell fates, aggregates of small molecules are able to serve as functional molecular entities in cellular environments. However, the inability to precisely control their production has hampered the understanding and exploration of their biological functions. Here we show that the well-established ligand-receptor interaction between vancomycin and d-Ala-d-Ala catalyzes the aggregation ...[more]

PMID: 25522243

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Project description:Chemical equilibria of multimerizations in systems with small numbers of particles exhibit a behavior seemingly at odds with that observed macroscopically. In this paper, we apply the recently proposed expression of equilibrium constant for binding, which includes cross-correlations in reactants' concentrations, to write an equilibrium constant for the formation of clusters larger than two (e.g., trimer, tetramer, and pentamer) as series of two-body reactions. Results obtained by molecular dynamics simulations demonstrate that the value of this expression is constant for all concentrations and system sizes, as well as at an onset of a phase transition to an aggregated state, where densities in the system change discontinuously. In contrast, the value of the commonly utilized expression of equilibrium constant, which ignores correlations, is not constant and its variations can reach few orders of magnitude. Considering different paths for the same multimer formation, with elementary reactions of any order, yields different expressions for the equilibrium constant, yet, with exactly the same value. This is also true for routes with essentially zero probability to occur. Existence of different expressions for the same equilibrium constant imposes equalities between averages of correlated, along with uncorrelated, concentrations of participating species. Moreover, a relation between an average particle number and relative fluctuations derived for two-body reactions is found to be obeyed here as well despite couplings to additional equilibrium reactions in the system. Analyses of transfer reactions, where association and dissociation events take place on both sides of the chemical equation, further indicate the necessity to include cross-correlations in the expression of the equilibrium constant. However, in this case, the magnitudes of discrepancies of the uncorrelated expression are smaller, likely because of partial cancellation of correlations, which exist on both the reactant and product sides.

Dataset Information

Ligand-receptor interaction catalyzes the aggregation of small molecules to induce cell necroptosis.

Publications

Ligand-receptor interaction catalyzes the aggregation of small molecules to induce cell necroptosis.

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