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Computational study of aggregation mechanism in human lysozyme[D67H]
Dharmeshkumar Patel1, Serdar Kuyucak1
1School of Physics, University of Sydney, Sydney, New South Wales 2006, Australia.
Plos One
|May 4, 2017
Summary
Protein aggregation, a health and biotech issue, is studied via molecular dynamics (MD) simulations. This research explains how a single mutation causes human lysozyme aggregation and offers a method to prevent it.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Biology
Background:
- Protein aggregation is a significant problem in human health and biotechnology, impacting therapeutic proteins.
- Dimer formation is the initial step in protein aggregation, making its study crucial for developing preventative measures.
Purpose of the Study:
- To investigate the molecular mechanisms of dimer formation in human lysozyme and its D67H variant using molecular dynamics (MD).
- To develop and validate an MD-based approach for predicting and understanding protein aggregation propensity.
Main Methods:
- High-temperature MD simulations to generate partially unfolded protein conformers.
- Protein-protein docking and further MD refinement to identify potential dimer structures.
- Free energy calculations to determine the stability of dimer formations.
Main Results:
- A detailed molecular-level explanation for the conversion of non-aggregating human lysozyme to an aggregating D67H variant.
- Identification of the specific role of the D67H mutation in promoting dimer formation and subsequent aggregation.
- Validation of the proposed MD approach for analyzing protein aggregation.
Conclusions:
- The study elucidates the structural basis of aggregation in human lysozyme, driven by a single mutation.
- The presented MD methodology can predict aggregation-prone sites in proteins.
- This approach offers a strategy for protein engineering to prevent aggregation and improve biopharmaceutical stability.
