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Drude2019IDPC polarizable force field reveals structure-function relationship of insulin
Xiaochen Cui1, Zhuoqi Zheng1, Mueed Ur Rahman1
1State Key Laboratory of Microbial metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Department of Bioinformatics and Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
International Journal of Biological Macromolecules
|October 4, 2024
Summary
A new Drude2019IDPC force field improves simulations of intrinsically disordered proteins (IDPs) and their associated diseases. This enhanced model provides better insights into protein structure-function relationships.
Area of Science:
- Computational chemistry and biophysics.
- Protein dynamics and intrinsically disordered proteins (IDPs).
- Development of advanced molecular simulation force fields.
Background:
- Intrinsically disordered proteins (IDPs) lack stable structures but are crucial in biological processes and diseases.
- Polarizable force fields are advantageous for simulating IDPs due to their conformational flexibility and charged residues.
- The Drude2019IDP force field showed promise but underestimated the simulation performance for five specific dipeptides.
Purpose of the Study:
- To enhance the Drude2019IDP force field for improved simulation accuracy of intrinsically disordered proteins (IDPs).
- To refine the force field's performance on specific dipeptides and validate its efficacy across various IDP systems.
- To investigate the conformational dynamics and mutation effects in insulin using the improved force field.
Main Methods:
- Individual reweighting and grid-based energy correction map (CMAP) optimization for five dipeptides.
- Development of the enhanced Drude2019IDPC force field.
- Molecular dynamics (MD) simulations and Markov state model (MSM) analysis applied to wild-type and mutant insulin.
Main Results:
- The enhanced Drude2019IDPC force field demonstrated marked improvements in simulating dipeptides, short peptides, and a representative IDP compared to the original Drude2019IDP.
- MD simulations and MSM analysis revealed that specific mutations in insulin can maintain monomorphic characteristics, offering insights into engineered insulin.
- The improved force field accurately captured conformational differences between wild-type and mutant insulin.
Conclusions:
- The Drude2019IDPC force field represents a significant advancement for accurately simulating intrinsically disordered proteins (IDPs).
- This enhanced force field can elucidate structure-function relationships in IDPs and aid in the development of engineered proteins like insulin.
- The findings support the broader applicability of Drude2019IDPC for studying diverse protein systems and their roles in health and disease.
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