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Sequence Specificity in the Entropy-Driven Binding of a Small Molecule and a Disordered Peptide
Gabriella T Heller1, Francesco A Aprile1, Massimiliano Bonomi1
1Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Journal of Molecular Biology
|July 27, 2017
Summary
Researchers discovered a "specific-diffuse" binding mechanism in disordered proteins, offering new drug development opportunities. This mechanism shows sequence specificity, potentially targeting disease-linked proteins in their monomeric states.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Intrinsically disordered proteins (IDPs) constitute a significant portion of the human proteome.
- IDPs are implicated in numerous diseases, yet their small molecule binding mechanisms and specificity for drug development are poorly understood.
Purpose of the Study:
- To elucidate the binding mechanism between small molecules and disordered proteins.
- To investigate the sequence specificity of this binding mechanism.
- To explore the potential of this mechanism for targeting disordered proteins in drug discovery.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy
- Biophysical measurements
- Statistical inference
- Molecular simulations
- Studied the interaction between a small molecule and a disordered peptide from the oncogene protein c-Myc.
Main Results:
- Described a novel "specific-diffuse" binding mechanism with sequence specificity, despite its entropic nature.
- Quantitatively measured sequence specificity and compared it to non-specific binding (urea).
- Demonstrated that this binding mechanism inhibits peptide aggregation, suggesting modulation of intermolecular interactions.
Conclusions:
- The "specific-diffuse" binding mechanism offers a new paradigm for understanding small molecule interactions with disordered proteins.
- This mechanism provides a basis for developing drugs that specifically target disordered proteins in their monomeric states.
- Highlights potential for novel therapeutic strategies against diseases associated with disordered proteins.
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