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Influence of Binding Site Affinity Patterns on Binding of Multivalent Polymers.

ABSTRACT: Using inspiration from biology, we can leverage multivalent binding interactions to enhance weak, monovalent binding between molecules. While most previous studies have focused on multivalent binders with uniform binding sites, new synthetic polymers might find it desirable to have multiple binding moieties along the chain. Here, we probe how patterning of heterogeneous binding sites along a polymer chain controls the binding affinity of a polymer using a reactive Brownian dynamics scheme. Unlike monovalent binders that are pattern-agnostic, we find that divalent binding is dependent on both the polymer pattern and binding target concentration. For dilute targets, blocky polymers provide high local concentrations of high-affinity sites, but at high target concentrations, competition for binding sites makes alternating polymers the strongest binders. Subsequently, we show that random copolymers are robust to target concentration fluctuations. These results will assist in the rational design of multivalent polymer therapeutics and materials.

SUBMITTER: Zumbro E

PROVIDER: S-EPMC7240832 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Influence of Binding Site Affinity Patterns on Binding of Multivalent Polymers.

Zumbro Emiko E Alexander-Katz Alfredo A

ACS omega 20200506 19

Using inspiration from biology, we can leverage multivalent binding interactions to enhance weak, monovalent binding between molecules. While most previous studies have focused on multivalent binders with uniform binding sites, new synthetic polymers might find it desirable to have multiple binding moieties along the chain. Here, we probe how patterning of heterogeneous binding sites along a polymer chain controls the binding affinity of a polymer using a reactive Brownian dynamics scheme. Unlik ...[more]

PMID: 32455197

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Project description:BackgroundPregnane X receptor (PXR) agonists inhibit liver fibrosis. However, the rodent PXR activator pregnenolone 16alpha carbonitrile (PCN) blocks, in vitro, hepatic stellate cell-to-myofibroblast trans-differentiation and proliferation in cells from mice with a disrupted PXR gene, suggesting there is an additional anti-fibrogenic drug target for PCN. The role of the low affinity glucocorticoid binding site (LAGS) - which may be identical or associated with the progesterone receptor membrane component 1 (PGRMC1) - in mediating this anti-fibrogenic effect has been examined, since binding of dexamethasone to the LAGS in liver microsomal membranes has previously been shown to be inhibited by PCN.ResultsQuiescent rat and human hepatic stellate cells (HSC) were isolated from livers and cultured to generate liver myofibroblasts. HSC and myofibroblasts expressed PGRMC1 as determined by RT-PCR and Western blotting. Quiescent rat HSC also expressed the truncated HC5 variant of rPGRMC1. Rat PGRMC1 was cloned and expression in COS-7 cells gave rise to specific binding of radiolabelled dexamethasone in cell extracts that was inhibited by PCN, suggesting that PGRMC1 may be identical to LAGS or activates LAGS binding activity. Liver microsomes were used to screen a range of structurally related compounds for their ability to inhibit radiolabelled dexamethasone binding to rat LAGS. These compounds were also screened for their ability to activate rat and human PXR and to inhibit rat HSC-to-myofibroblast trans-differentiation/proliferation. A compound (4 androstene-3-one 17beta-carboxylic acid methyl ester) was identified which bound rat LAGS with high affinity and inhibited both rat and human HSC trans-differentiation/proliferation to fibrogenic myofibroblasts without showing evidence of rat or human PXR agonism. However, despite potent anti-fibrogenic effects in vitro, this compound did not modulate liver fibrosis severity in a rat model of liver fibrosis. Immunohistochemical analysis showed that rat liver myofibroblasts in vivo did not express rPGRMC1.ConclusionLAGS ligands inhibit HSC trans-differentiation and proliferation in vitro but show little efficacy in inhibiting liver fibrosis, in vivo. The reason(s) for this disparity is/are likely associated with an altered myofibroblast phenotype, in vitro, with expression of rPGMRC1 in vitro but not in vivo. These data emphasize the limitations of in vitro-derived myofibroblasts for predicting their activity in vivo, in studies of fibrogenesis. The data also demonstrate that the anti-fibrogenic effects of PCN in vivo are likely mediated entirely via the PXR.

Dataset Information

Influence of Binding Site Affinity Patterns on Binding of Multivalent Polymers.

Publications

Influence of Binding Site Affinity Patterns on Binding of Multivalent Polymers.

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