Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Letter
Hydrophobic Association in Mixed Urea-TMAO Solutions Pritam Ganguly, Nico F. A. van der Vegt, and Joan-Emma Shea J. Phys. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acs.jpclett.6b01344 • Publication Date (Web): 21 Jul 2016 Downloaded from http://pubs.acs.org on July 26, 2016
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Physical Chemistry Letters is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 8
The Journal of Physical Chemistry Letters
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment
The Journal of Physical Chemistry Letters
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
osmolyte solutions. In this context it is highly relevant to further raise the question of how urea and TMAO effect hydrophobic interactions in mixed urea-TMAO environments. Indeed, hydrophobic interactions between the nonpolar groups of proteins contribute significantly to the stability of the folded conformations of proteins. 26,27 The effects of urea on hydrophobic associations have been rigorously studied through experiments and computer simulations, 28–36 yet a unifying mechanism through which urea alters hydrophobic interactions has not been established. Solubility of small hydrocarbons increases upon addition of urea into pure water except for the smallest hydrocarbon methane where the transfer free-energy from water to ureawater mixture was found to be positive. 29,37 It has been argued that urea increases the solubility of the hydrocarbons by dissolving the hydrophobic clusters, while an enhancement of methane clustering at high urea concentrations has also been reported. 38 In this context, Lee and van der Vegt have shown that urea does not completely disrupt hydrophobic interactions between neopentane molecules, rather urea molecules act as bridges between the hydrophobic molecules. This reduces neopentane-neopentane contact pairs, leading to swelling of the hydrophobic clusters. 35 For larger hydrocarbons the effects of urea on the hydrophobic interactions are ambiguous and the inferences vary among different studies. In contrast to urea, there exist significantly fewer studies considering the effects of TMAO on hydrophobic association. In simulation studies of small hydrophobic solutes and hydrophobic chains in TMAO solutions Athawale et al. have shown that TMAO does not have any significant effect on hydrophobic interactions. 39 In contrast, Paul and Patey have reported that TMAO disrupts hydrophobic interactions between neopentane pairs. 40,41 TMAO has been found to promote the folded conformations of hydrophobic chains 42,43 while at the same time preferentially interacting with these hydrophobic chains 42,43 as well as with small hydrophobic solutes 44 over water. This is counter to an alternative school of thought in which protecting osmolytes are believed to be excluded from the protein surfaces. 10,45 An increase in TMAO’s preferential interactions with the hydrophobic chains upon folding has been shown in simulation, and this may contribute to TMAO’s ability to protect the folded structures of the chains. 42,43 On the other hand, vibrational sum frequency spectroscopy measurements have proposed depletion of TMAO from hydrophobic surfaces. 46 At this point it is important to note that all the computational studies mentioned above that consider TMAO’s effects on hydrophobic association and interactions have used one particular TMAO forcefield, developed by Kast et al 47 (referred as the Kast model henceforth). The Kast model for TMAO was developed using quantum ab initio calculations without validating its compatibility with water models. In TMAO-water mixtures, the Kast model for TMAO shows higher TMAO-TMAO aggregation and weaker TMAO-water affinity than experiment, which in turns leads to an underestimation of the activity coefficient of TMAO. 15,48 In order to overcome the deficiencies in the Kast model, two other TMAO force-fields have recently been developed with the goal of reproducing experimental activity or osmotic pressure of TMAO. The model developed by Netz and coworkers (referred as the Netz model in this paper) primarily uses the parameters of the Kast model but employs a higher N-O dipole moment for more hydrophilicity, in conjunction with increased hydrophobicity of the methyl groups. 48 The other TMAO force-field, developed by Garc´ıa and coworkers (identified as the Garcia model in this manuscript) is also based on the Kast force-field but with an enhanced charge distribution, to impart a higher water affinity for TMAO and a reduced attractive van der Waals interaction between the TMAO molecules. Together, these modifications yield a higher osmotic pressure of TMAO-water solutions over the Kast model. 15
Page 2 of 8
In this manuscript, we address the question of TMAO’s effect on the solvation thermodynamics of hydrophobic molecules in the presence of urea. Using molecular dynamics simulations we show that the choice of TMAO force-field (Kast, Netz or Garcia models) has a dramatic impact on the association of hydrophobic molecules, in intriguing contrast to our previous study that showed little effect of force field selection on amino acid monomers in urea-TMAO solutions. 25 A detailed comparison between the results obtained from the different TMAO force-fields allows us to identify the role of TMAO hydrophilicity and osmolyte-osmolyte affinity in determining whether hydrophobic molecules aggregate or dissociate in mixed osmolyte solutions. Here we study the model hydrophobe neopentane at dilute concentration ( 0 or G13 > G12 indicates preferential binding of the solute to the cosolvent over the solvent. To determine the preferential binding or exclusion of the cosolvents (urea or TMAO) near hydrophobic molecules, we plot neopentane-water and neopentane-cosolvent KBIs in Figure 1. Comparing neopentane-TMAO KBIs (Gnt ) and neopentane-water KBIs (Gnw ) we find that the preferential binding of TMAO to neopentane strongly depends on the choice of TMAO models. At 4 M TMAO solutions, TMAO preferentially binds to neopentane as Gnt > Gnw when the Kast and the Garcia models are used. This is qualitatively consistent with the results obtained from hydrophobic chains in TMAO solutions where the Kast model has been used. 42,43 But when the Netz model for TMAO is used, the TMAO molecules tend to deplete more from the neopentane surface (reduction in neopentaneTMAO KBI) and are preferentially excluded from neopentane as Gnt < Gnw . The change in the preferential interaction between TMAO and neopentane with the change in the TMAO force-field is intriguing and shows us that any mechanism proposed on the basis of preferential binding of TMAO with hydrophobes should be made with a caution. However the effect of urea on neopentane-TMAO association is qualitatively independent of the TMAO models, and TMAO molecules are depleted from neopentane when 8 M Urea is added to a 4 M TMAO solution. In 8 M urea solutions, urea preferentially accumulates near the neopentane surface. Addition of 4 M TMAO to 8 M urea has TMAO force-field dependent effects on neopentane-urea preferential binding. Urea molecules are depleted from neopentane when the Kast model of TMAO is used while the Netz TMAO model pushes more urea molecules to accumulate near neopentane surfaces (shown by neopentane-urea KBIs, Gnu , in Figure 1). Corresponding spatial distributions of urea around neopen-
ACS Paragon Plus 2 Environment
Page 3 of 8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Physical Chemistry Letters
Figure 2: Shown are the urea-TMAO (Gut ) and TMAO-water (Gtw ) Kirkwood-Buff integrals for a mixed 8 M urea and 4 M TMAO solution containing neopentane. The results are compared for three different TMAO models, namely the Kast, the Netz and the Garcia. For Kast and Netz force-fields SPC/E water and for Garcia force-field TIP3P water have been used. The Kast model strongly binds to urea while the Netz model strongly binds to water; the Garcia model in turns interacts strongly to both urea and water.
Figure 1: Upper panel: Kirkwood-Buff integrals (KBIs) between neopentane and urea (Gnu ) and between neopentane and water (Gnw ) for neopentane in 8 M urea and mixed 8 M urea and 4 M TMAO solutions. Lower panel: KBIs between neopentane and TMAO (Gnt ) and between neopentane and water (Gnw ) for neopentane in 4 M TMAO and mixed 8 M urea and 4 M TMAO solutions. The results are compared using three TMAO models: Kast, Netz and Garcia. For Kast and Netz force-fields SPC/E water and for Garcia force-field TIP3P water have been used. Combination rules for Lennard-Jones cross√ interactions: σij = σi σj for Kast and Netz labels and σij = (σi + σj )/2 for Garcia labels. Note: the results with 8 M urea differ under Garcia labels from Kast or Netz labels. The error-bars show the maximum error associated with the KBI types: ∆Gnu
