Insight into the Molecular Mechanisms of Protein Stabilizing Osmolytes from Global Force-Field Variations
Abstract
A prominent class of osmolytes that are able to stabilize proteins in their native fold consist of small highly water-soluble molecules with a large dipole moment and hydrophobic groups attached to the positively charged end of the molecule, for which we coin the term dipolar/hydrophobic osmolytes. For TMAO, which is a prime member of this class, we perform large-scale water-explicit MD simulations and determine the bulk solution activity coefficient as well as the affinity to a stretched polyglycine chain for varying TMAO dipolar strength and hydrophobicity. Double optimization with respect to experimental values for the activity coefficient and the polyglycine transfer free energy is achieved. The resulting optimal TMAO force field shows excellent transferability to different concentrations and also reproduces transfer free energies of various amino acids, including the tryptophan anomaly, for which TMAO acts as a denaturant. By globally analyzing the thermodynamic and structural properties of suboptimal TMAO force fields, we identify the frustration between dipolar and hydrophobic interactions as the working mechanism and the design principle of dipolar/hydrophobic osmolytes.
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TMAO behaves as a chaotropic agent, with the ability to alter protein conformation and potentially serve as an allosteric modulator to proteins.
“Due to its small size and combination of hydrophilic and hydrophobic properties, TMAO behaves as a chaotropic agent, with the ability to alter protein conformation and potentially serve as an allosteric modulator to proteins134.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [134]
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- Authors
- Schneck, E., Horinek, D., & Netz, R. R.
- Affiliations
- Technical University of Munich (DE)
- University of Regensburg (DE)
- Corresponding author
- Netz, Roland R.
- Venue
- The Journal of Physical Chemistry B
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-07-03
- Volume
- 117
- Issue
- 28
- Pages
- 8310-8321
- ISSN
- 1520-5207 (ISSN-L)
- 1520-6106
- OpenAlex
- W2330139490
- Cited by
- 115
- References
- 57
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 6 · 2022: 10 · 2021: 8 · 2020: 10 · 2019: 12 · 2018: 11 · 2017: 19 · 2016: 15 · 2015: 6 · 2014: 2
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Physical Chemistry B (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- TUbilio (Technical University of Darmstadt) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Advanced Physical and Chemical Molecular Interactions
- Physical Sciences › Physics and Astronomy › Atomic and Molecular Physics, and Optics › Advanced Chemical Physics Studies
- Keywords
- osmolytes, trimethylamine N-oxide, protein stabilization, force field optimization, activity coefficients, protein folding
- MeSH terms
- Methylamines, Proteins, Solvents, Thermodynamics, Protein Folding, Protein Stability, Hydrophobic and Hydrophilic Interactions
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