Osmolyte Trimethylamine-N-Oxide Does Not Affect the Strength of Hydrophobic Interactions: Origin of Osmolyte Compatibility
Open accessAbstract
Osmolytes are small organic solutes accumulated at high concentrations by cells/tissues in response to osmotic stress. Osmolytes increase thermodynamic stability of folded proteins and provide protection against denaturing stresses. The mechanism of osmolyte compatibility and osmolyte-induced stability has, therefore, attracted considerable attention in recent years. However, to our knowledge, no quantitative study of osmolyte effects on the strength of hydrophobic interactions has been reported. Here, we present a detailed molecular dynamics simulation study of the effect of the osmolyte trimethylamine-N-oxide (TMAO) on hydrophobic phenomena at molecular and nanoscopic length scales. Specifically, we investigate the effects of TMAO on the thermodynamics of hydrophobic hydration and interactions of small solutes as well as on the folding-unfolding conformational equilibrium of a hydrophobic polymer in water. The major conclusion of our study is that TMAO has almost no effect either on the thermodynamics of hydration of small nonpolar solutes or on the hydrophobic interactions at the pair and many-body level. We propose that this neutrality of TMAO toward hydrophobic interactions-one of the primary driving forces in protein folding-is at least partially responsible for making TMAO a "compatible" osmolyte. That is, TMAO can be tolerated at high concentrations in organisms without affecting nonspecific hydrophobic effects. Our study implies that protein stabilization by TMAO occurs through other mechanisms, such as unfavorable water-mediated interaction of TMAO with the protein backbone, as suggested by recent experimental studies. We complement the above calculations with analysis of TMAO hydration and changes in water structure in the presence of TMAO molecules. TMAO is an amphiphilic molecule containing both hydrophobic and hydrophilic parts. The precise balance of the effects of hydrophobic and hydrophilic segments of the molecule appears to explain the virtual noneffect of TMAO on the strength of hydrophobic interactions.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TMAO preserves the folded state of proteins and counteracts denaturants such as pH, urea, and high pressure.
“It retains the folded state of proteins and counteracts the effect of denaturants, such as pH, urea, and high pressure (6,13,29).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [6]
Cites
Molecular dynamics with coupling to an external bath
Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F., DiNola, A., & Haak, J. R. (1984) · The Journal of Chemical Physics · doi:10.1063/1.448118 · Cited by 30,626 · see citing works
Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems
Darden, T., York, D., & Pedersen, L. (1993) · The Journal of Chemical Physics · doi:10.1063/1.464397 · Cited by 29,588 · see citing works
Computer Simulation of Liquids
Allen, M. P., & Tildesley, D. J. (2017) · doi:10.1093/oso/9780198803195.001.0001 · Cited by 20,945 · see citing works
Computer Simulation of Liquids
P, S., & J, K. (1988) · Journal of Molecular Liquids · doi:10.1016/0167-7322(88)80022-9 · Cited by 16,084 · see citing works
The missing term in effective pair potentials
Berendsen, H. J. C., Grigera, J. R., & Straatsma, T. P. (1987) · The Journal of Physical Chemistry · doi:10.1021/j100308a038 · Cited by 13,313 · see citing works
GROMACS: A message-passing parallel molecular dynamics implementation
Berendsen, H. J. C., van der Spoel, D., & van Drunen, R. (1995) · Computer Physics Communications · doi:10.1016/0010-4655(95)00042-e · Cited by 10,748 · see citing works
Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models
Miyamoto, S., & Kollman, P. A. (1992) · Journal of Computational Chemistry · doi:10.1002/jcc.540130805 · Cited by 7,268 · see citing works
GROMACS 3.0: a package for molecular simulation and trajectory analysis
Lindahl, E. R., Hess, B., & van der Spoel, D. (2001) · Journal of Molecular Modeling · doi:10.1007/s008940100045 · Cited by 6,953 · see citing works
Understanding Molecular Simulation
Frenkel, D., Smit, B., Tobochnik, J., McKay, S. R., & Christian, W. (1997) · Computers in Physics · doi:10.1063/1.4822570 · Cited by 5,395 · see citing works
Some Factors in the Interpretation of Protein Denaturation
Kauzmann, W. (1959) · Advances in protein chemistry · doi:10.1016/s0065-3233(08)60608-7 · Cited by 4,880 · see citing works
Dominant forces in protein folding
Dill, K. A. (1990) · Biochemistry · doi:10.1021/bi00483a001 · Cited by 3,824 · see citing works
Living with Water Stress: Evolution of Osmolyte Systems
Yancey, P. H., Clark, M. E., Hand, S. C., Bowlus, R. D., & Somero, G. N. (1982) · Science · doi:10.1126/science.7112124 · Cited by 3,724 · see citing works
The Hydrophobic Effect: Formation of Micelles and Biological Membranes
Tanford, C. (1991) · Medical Entomology and Zoology · Cited by 3,331 · see citing works
The Hydrophobic Effect: Formation of Micelles and Biological Membranes
Walker, C. H. (1981) · FEBS Letters · doi:10.1016/0014-5793(81)80071-3 · Cited by 2,712 · see citing works
Optimized Monte Carlo data analysis
Ferrenberg, A. M., & Swendsen, R. H. (1989) · Physical Review Letters · doi:10.1103/physrevlett.63.1195 · Cited by 2,613 · see citing works
Some Topics in the Theory of Fluids
Widom, B. (1963) · The Journal of Chemical Physics · doi:10.1063/1.1734110 · Cited by 2,553 · see citing works
Understanding Molecular Simulation
(2002) · doi:10.1016/b978-0-12-267351-1.x5000-7 · Cited by 2,042 · see citing works
Relationship between structural order and the anomalies of liquid water
Errington, J. R., & Debenedetti, P. G. (2001) · Nature · doi:10.1038/35053024 · Cited by 1,642 · see citing works
Is Random Close Packing of Spheres Well Defined?
Torquato, S., Truskett, T. M., & Debenedetti, P. G. (2000) · Physical Review Letters · doi:10.1103/physrevlett.84.2064 · Cited by 1,384 · see citing works
Stabilization of protein structure by sugars
Arakawa, T., & Timasheff, S. N. (1982) · Biochemistry · doi:10.1021/bi00268a033 · Cited by 1,089 · see citing works
The stabilization of proteins by osmolytes
Arakawa, T., & Timasheff, S. N. (1985) · Biophysical Journal · doi:10.1016/s0006-3495(85)83932-1 · Cited by 1,024 · see citing works
Theory of the hydrophobic effect
Pratt, L. R., & Chandler, D. (1977) · The Journal of Chemical Physics · doi:10.1063/1.435308 · Cited by 837 · see citing works
Arakawa, T., & Timasheff, S. N. (1984) · Biochemistry · doi:10.1021/bi00320a004 · Cited by 674 · see citing works
Bolen, D. W., & Baskakov, I. V. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2001.4819 · Cited by 658 · see citing works
A new order parameter for tetrahedral configurations
Chau, P. ‐., & Hardwick, A. J. (1998) · Molecular Physics · doi:10.1080/002689798169195 · Cited by 561 · see citing works
Potential-distribution theory and the statistical mechanics of fluids
Widom, B. (1982) · The Journal of Physical Chemistry · doi:10.1021/j100395a005 · Cited by 537 · see citing works
Osmotic stress, crowding, preferential hydration, and binding: A comparison of perspectives
Parsegian, V. A., Rand, R. P., & Rau, D. C. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.8.3987 · Cited by 491 · see citing works
The Peptide Backbone Plays a Dominant Role in Protein Stabilization by Naturally Occurring Osmolytes
Liu, Y., & Bolen, D. W. (1995) · Biochemistry · doi:10.1021/bi00039a051 · Cited by 457 · see citing works
Wang, A., & Bolen, D. W. (1997) · Biochemistry · doi:10.1021/bi970247h · Cited by 448 · see citing works
Zou, Q., Bennion, B. J., Daggett, V., & Murphy, K. P. (2002) · Journal of the American Chemical Society · doi:10.1021/ja004206b · Cited by 446 · see citing works
Schellman, J. A. (1978) · Biopolymers · doi:10.1002/bip.1978.360170515 · Cited by 389 · see citing works
Hydrophobic Effects and Modeling of Biophysical Aqueous Solution Interfaces
Pratt, L. R., & Pohorille, A. (2002) · Chemical Reviews · doi:10.1021/cr000692+ · Cited by 380 · see citing works
Lin, T.-Y., & Timasheff, S. N. (1994) · Biochemistry · doi:10.1021/bi00208a021 · Cited by 371 · see citing works
Forcing Thermodynamically Unfolded Proteins to Fold
Baskakov, I. V., & Bolen, D. W. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.9.4831 · Cited by 358 · see citing works
Bennion, B. J., & Daggett, V. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308633101 · Cited by 310 · see citing works
Selective binding and solvent denaturation
Schellman, J. A. (1987) · Biopolymers · doi:10.1002/bip.360260408 · Cited by 310 · see citing works
Contribution of the Surface Free Energy Perturbation to Protein-Solvent Interactions
Kita, Y. A., Arakawa, T., Lin, T.-Y., & Timasheff, S. N. (1994) · Biochemistry · doi:10.1021/bi00254a029 · Cited by 300 · see citing works
Truskett, T. M., Torquato, S., & Debenedetti, P. G. (2000) · Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics · doi:10.1103/physreve.62.993 · Cited by 296 · see citing works
Drying-induced hydrophobic polymer collapse
ten Wolde, P. R., & Chandler, D. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052153299 · Cited by 290 · see citing works
Yancey, P. H., Blake, W. R., & Conley, J. (2002) · Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology · doi:10.1016/s1095-6433(02)00182-4 · Cited by 218 · see citing works
Shimizu, S. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0305836101 · Cited by 202 · see citing works
Water Stress, Osmolytes and Proteins1
Yancey, P. H. (2001) · American Zoologist · doi:10.1668/0003-1569(2001)041[0699:wsoap]2.0.co;2 · Cited by 193 · see citing works
Salting-In and Salting-Out of Hydrophobic Solutes in Aqueous Salt Solutions
Kalra, A., Tugçu, N., Cramer, S. M., & Garde, S. (2001) · The Journal of Physical Chemistry B · doi:10.1021/jp010568+ · Cited by 188 · see citing works
Self-citation(1992) · doi:10.1007/978-3-642-76682-4 · Cited by 182 · see citing works
Perturbation theory for the thermodynamic properties of simple liquids
Verlet, L., & Weis, J. J. (1972) · Molecular Physics · doi:10.1080/00268977200102111 · Cited by 173 · see citing works
Size dependent ion hydration, its asymmetry, and convergence to macroscopic behavior
Rajamani, S., Ghosh, T., & Garde, S. (2004) · The Journal of Chemical Physics · doi:10.1063/1.1644536 · Cited by 170 · see citing works
Self-citationProteins in Mixed Solvents: A Molecular-Level Perspective
Baynes, B. M., & Trout, B. L. (2003) · The Journal of Physical Chemistry B · doi:10.1021/jp0363996 · Cited by 167 · see citing works
Molecular Dynamics Simulations of Pressure Effects on Hydrophobic Interactions
Ghosh, T., Garcı́a, A. E., & Garde, S. (2001) · Journal of the American Chemical Society · doi:10.1021/ja010446v · Cited by 159 · see citing works
Self-citationPreferential interactions of urea with lysozyme and their linkage to protein denaturation
Timasheff, S. N., & Xie, G. (2003) · Biophysical Chemistry · doi:10.1016/s0301-4622(03)00106-6 · Cited by 151 · see citing works
Cavity Expulsion and Weak Dewetting of Hydrophobic Solutes in Water
Hummer, G., & Garde, S. (1998) · Physical Review Letters · doi:10.1103/physrevlett.80.4193 · Cited by 135 · see citing works
Self-citationKast, K. M., Brickmann, J., Kast, S. M., & Berry, R. S. (2003) · The Journal of Physical Chemistry A · doi:10.1021/jp027336a · Cited by 133 · see citing works
Effects of solute–solvent attractive forces on hydrophobic correlations
Pratt, L. R., & Chandler, D. (1980) · The Journal of Chemical Physics · doi:10.1063/1.440541 · Cited by 130 · see citing works
On the Salt-Induced Stabilization of Pair and Many-body Hydrophobic Interactions
Ghosh, T., Kalra, A., & Garde, S. (2004) · The Journal of Physical Chemistry B · doi:10.1021/jp0475638 · Cited by 129 · see citing works
Self-citationTemperature dependence of the solubility of non-polar gases in water
Garde, S., Garcı́a, A. E., Pratt, L. R., & Hummer, G. (1999) · Biophysical Chemistry · doi:10.1016/s0301-4622(99)00018-6 · Cited by 111 · see citing works
Self-citationComputer Simulation of Cosolvent Effects on Hydrophobic Hydration
Smith, P. E. (1998) · The Journal of Physical Chemistry B · doi:10.1021/jp983303c · Cited by 94 · see citing works
Enthalpy and entropy contributions to the pressure dependence of hydrophobic interactions
Ghosh, T., Garcı́a, A. E., & Garde, S. (2002) · The Journal of Chemical Physics · doi:10.1063/1.1431582 · Cited by 86 · see citing works
Self-citationBeutler, T. C., & van Gunsteren, W. F. (1994) · The Journal of Chemical Physics · doi:10.1063/1.466628 · Cited by 81 · see citing works
Preventing Misfolding of the Prion Protein by Trimethylamine N-Oxide
Bennion, B. J., DeMarco, M. L., & Daggett, V. (2004) · Biochemistry · doi:10.1021/bi0486379 · Cited by 79 · see citing works
Free energy of hydration of a molecular ionic solute: Tetramethylammonium ion
Garde, S., Hummer, G., & Paulaitis, M. E. (1998) · The Journal of Chemical Physics · doi:10.1063/1.475526 · Cited by 65 · see citing works
Self-citationGhosh, T., Garcı́a, A. E., & Garde, S. (2002) · The Journal of Physical Chemistry B · doi:10.1021/jp0220175 · Cited by 55 · see citing works
Self-citationAshbaugh, H. S. (2003) · Biophysical Chemistry · doi:10.1016/s0301-4622(03)00084-x · Cited by 49 · see citing works
Garde, S., Hummer, G., & Paulaitis, M. E. (1996) · Faraday Discussions · doi:10.1039/fd9960300125 · Cited by 38 · see citing works
Self-citationA new configuration interaction algorithm for electron-spindependent properties
PALMIERI, B. A. O. M. A. P. (1997) · Molecular Physics · doi:10.1080/002689797170266 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease
Zeisel, S. H., & Warrier, M. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064732 · Cited by 475 · see citing works
Schneck, E., Horinek, D., & Netz, R. R. (2013) · The Journal of Physical Chemistry B · doi:10.1021/jp400790f · Cited by 115 · see citing works
Trimethylamine N-oxide suppresses the activity of the actomyosin motor
Kumemoto, R., Yusa, K., Shibayama, T., & Hatori, K. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.06.006 · Cited by 31 · see citing works
- Authors
- Athawale, M. V., Dordick, J. S., & Garde, S.
- Affiliations
- Rensselaer Polytechnic Institute (US)
- Corresponding author
- Garde, Shekhar
- Venue
- Biophysical Journal
- Publisher
- Elsevier BV
- Published
- 2005-08
- Volume
- 89
- Issue
- 2
- Pages
- 858-866
- ISSN
- 0006-3495 (ISSN-L)
- PMC
- PMC1366635
- OpenAlex
- W2076360029
- Cited by
- 153
- References
- 64
- Citations by year
- 2025: 9 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 9 · 2016: 12 · 2015: 15 · 2014: 4 · 2013: 14 · 2012: 14
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biophysical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM66712, R01GM066712)
- 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 › Spectroscopy and Quantum Chemical Studies
- Keywords
- trimethylamine N-oxide, osmolytes, hydrophobic interactions, hydrophobic hydration, protein folding, protein stabilization, water structure, osmotic stress
- MeSH terms
- Computer Simulation, Methylamines, Models, Chemical, Models, Molecular, Molecular Conformation, Osmosis, Polymers, Solubility, Solutions, Solvents, Water, Hydrophobic and Hydrophilic Interactions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
