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Molecular basis of lateral force spectroscopy nano-diagnostics: computational unbinding of autism related chemokine MCP-1 from IgG antibody.

ABSTRACT: Monocyte-chemoattractant protein-1 (MCP-1), also known as CCL2, is a potent chemoattractant of T cells and monocytes, involved in inflammatory and angio-proliferative brain and retinal diseases. Higher expression of MCP-1 is observed in metastatic tumors. Unusual levels of MCP-1 in the brain may be correlated with autism. Immunochemistry where atomic force microscope (AFM) tips functionalized with appropriate antibodies against MCP-1 are used could in principle support medical diagnostics. Useful signals from single molecule experiments may be generated if interaction forces are large enough. The chemokine-antibody unbinding force depends on a relative motion of the interacting fragments of the complex. In this paper the stability of the medically important MCP-1- immunoglobulin G antibody Fab fragment complex has been studied using steered molecular dynamics (SMD) computer simulations with the aim to model possible arrangements of nano-diagnostics experiments. Using SMD we confirm that molecular recognition in MCP1-IgG is based mainly on six pairs of residues: Glu39A - Arg98H, Lys56A - Asp52H, Asp65A - Arg32L, Asp68A - Arg32L, Thr32A - Glu55L, Gln61A - Tyr33H. The minimum external force required for mechanical dissociation of the complex depends on a direction of the force. The pulling of the MCP-1 antigen in the directions parallel to the antigen-antibody contact plane requires forces about 20 %-40 % lower than in the perpendicular one. Fortunately, these values are large enough that the fast lateral force spectroscopy may be used for effective nano-diagnostics purposes. We show that molecular modeling is a useful tool in planning AFM force spectroscopy experiments.

SUBMITTER: Gogolinska A

PROVIDER: S-EPMC3825506 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Molecular basis of lateral force spectroscopy nano-diagnostics: computational unbinding of autism related chemokine MCP-1 from IgG antibody.

Gogolinska Anna A Nowak Wieslaw W

Journal of molecular modeling 20130906 11

Monocyte-chemoattractant protein-1 (MCP-1), also known as CCL2, is a potent chemoattractant of T cells and monocytes, involved in inflammatory and angio-proliferative brain and retinal diseases. Higher expression of MCP-1 is observed in metastatic tumors. Unusual levels of MCP-1 in the brain may be correlated with autism. Immunochemistry where atomic force microscope (AFM) tips functionalized with appropriate antibodies against MCP-1 are used could in principle support medical diagnostics. Usefu ...[more]

PMID: 24061853

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Project description:Single-molecule force spectroscopy (SMFS) provides a powerful tool to explore the dynamics and energetics of individual proteins, protein-ligand interactions, and nucleic acid structures. In the canonical assay, a force probe is retracted at constant velocity to induce a mechanical unfolding/unbinding event. Next, two energy landscape parameters, the zero-force dissociation rate constant (ko) and the distance to the transition state (Δx‡), are deduced by analyzing the most probable rupture force as a function of the loading rate, the rate of change in force. Analyzing the shape of the rupture force distribution reveals additional biophysical information, such as the height of the energy barrier (ΔG‡). Accurately quantifying such distributions requires high-precision characterization of the unfolding events and significantly larger data sets. Yet, identifying events in SMFS data is often done in a manual or semiautomated manner and is obscured by the presence of noise. Here, we introduce, to our knowledge, a new algorithm, FEATHER (force extension analysis using a testable hypothesis for event recognition), to automatically identify the locations of unfolding/unbinding events in SMFS records and thereby deduce the corresponding rupture force and loading rate. FEATHER requires no knowledge of the system under study, does not bias data interpretation toward the dominant behavior of the data, and has two easy-to-interpret, user-defined parameters. Moreover, it is a linear algorithm, so it scales well for large data sets. When analyzing a data set from a polyprotein containing both mechanically labile and robust domains, FEATHER featured a 30-fold improvement in event location precision, an eightfold improvement in a measure of the accuracy of the loading rate and rupture force distributions, and a threefold reduction of false positives in comparison to two representative reference algorithms. We anticipate FEATHER being leveraged in more complex analysis schemes, such as the segmentation of complex force-extension curves for fitting to worm-like chain models and extended in future work to data sets containing both unfolding and refolding transitions.

Dataset Information

Molecular basis of lateral force spectroscopy nano-diagnostics: computational unbinding of autism related chemokine MCP-1 from IgG antibody.

Publications

Molecular basis of lateral force spectroscopy nano-diagnostics: computational unbinding of autism related chemokine MCP-1 from IgG antibody.

Similar Datasets

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