Physics-based modeling provides predictive understanding of selectively promiscuous substrate binding by Hsp70
Erik B Nordquist1, Charles A English2,3, Eugenia M Clerico2
1Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America.
Plos Computational Biology
|November 4, 2021
Summary
Heat shock proteins (Hsp70s) like E. coli DnaK bind diverse protein sequences through specific hydrophobic interactions. A new physics-based model, Paladin, accurately predicts DnaK substrate binding and configuration, offering insights into chaperone selectivity.
Area of Science:
- Molecular biology
- Biophysics
- Computational biology
Background:
- Hsp70 molecular chaperones are crucial for cellular protein homeostasis, preventing misfolding and aggregation.
- DnaK, the E. coli Hsp70, exhibits selective binding to a range of substrate sequences, a phenomenon termed 'selective promiscuity'.
- High-resolution structures reveal a conserved binding mode within DnaK's substrate-binding domain (SBD), involving five interaction sites for consecutive residues.
Purpose of the Study:
- To rationalize the observed selective promiscuity of DnaK binding.
- To develop a predictive model for DnaK-substrate interactions based on physical principles.
- To gain insights into the molecular basis of Hsp70-substrate recognition.
Main Methods:
- Atomistic molecular dynamics simulations were employed to analyze interactions between all 20 amino acid side chains and the five binding sites of DnaK.
- Interaction energetics from simulations were used to derive a physics-based predictive model named Paladin (Physics-based model of DnaK-Substrate Binding).
- Paladin was trained and validated using existing peptide array data and crystal structures of DnaK-peptide complexes.
Main Results:
- Paladin accurately distinguishes between DnaK binders and non-binders, achieving accuracy comparable to existing predictors.
- The model successfully predicts the detailed binding configuration of DnaK substrates.
- Paladin demonstrated high accuracy in predicting binding register and orientation for known DnaK-peptide complexes.
Conclusions:
- The physics-based Paladin model provides a mechanistic understanding of how Hsp70s achieve a balance of selectivity and promiscuity in substrate binding.
- The developed approach offers a framework for predicting Hsp70-substrate interactions, extendable to other Hsp70 family members.
- This study advances our understanding of chaperone-substrate recognition, crucial for protein quality control in cells.
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