Crowding Stabilizes DMSO â Water Hydrogen-Bonding Interactions

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B: Liquids, Chemical and Dynamical Processes in Solution, Spectroscopy in Solution

Crowding Stabilizes DMSO – Water Hydrogen-Bonding Interactions Kwang-Im Oh, and Carlos R Baiz J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b02739 • Publication Date (Web): 09 May 2018 Downloaded from http://pubs.acs.org on May 10, 2018

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The Journal of Physical Chemistry

Crowding Stabilizes DMSO – Water Hydrogenbonding Interactions Kwang-Im Oh+, Carlos R. Baiz*+ +Department of Chemistry, University of Texas at Austin, 105 E 24th St. Stop A5300 Austin, Texas 78712

ABSTRACT. Up to 40% of intracellular water is confined due to the dense packing of macromolecules, ions, and osmolytes. Despite the large body of work concerning the effect of additives on biomolecular structure and stability, the role of crowding and heterogeneity is not well understood. Here, infrared spectroscopy and molecular dynamics simulations are used to describe the mechanisms by which crowding modulates hydrogen bonding interactions between water and dimethyl sulfoxide (DMSO). Specifically, we use formamide and dimethylformamide (DMF) as molecular crowders and show that S=O hydrogen bond populations in aqueous mixtures are increased by both amides. These additives increase the amount of water within the DMSO first solvation shell through two mechanisms: a. directly stabilizing water-DMSO hydrogen bonds; b. increasing water exposure by destabilizing DMSO–DMSO self-interactions. Further, we quantified the hydrogen bond enthalpies between the different components: DMSO– water (61 kJ/mol) > DMSO–formamide (32 kJ/ mol) > water–water (23 kJ/mol) >> formamide– water (4.7 kJ/mol). Spectra of carbonyl stretching vibrations show that DMSO induces

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dehydration of amides as a result of strong DMSO–water interactions, which has been suggested as the main mechanism of protein destabilization.

Introduction Crowding and heterogeneity are hallmarks of biology at the molecular scale. The cell interior is densely packed; as much as 20-40% of intracellular water is confined by biomacromolecules or osmolytes.1-11 Crowding disrupts solvent hydrogen bond networks and modulates the hydration levels of proteins and osmolytes.12-17 Measuring these effects is challenging since a combination of structural sensitivity and chemical specificity is required. For these reasons, microscopic descriptions of complex mixtures, and the elements required to link solvent environments with biomolecular structure are not understood.18-21 Characterizing the effect of crowding on hydrogen bonding12,14-16,22 is the first step towards achieving a microscopic description of heterogeneous environments.23-26 Molecular dynamics (MD) simulations provide atomistic views of osmolyte or denaturant interactions12,18,27,28 and can predict protein stability semi-quantitatively.29-33 However, without direct experimental benchmarks, simulations can be subject to modeling bias.34-36 Building on our earlier work37 in which we measured dimethyl sulfoxide (DMSO)-water hydrogen bond populations, here we investigate the effects of small amides, as molecular crowders and simple amino-acid analogs. We show that crowding stabilizes hydrogen bonds in aqueous DMSO, a common denaturant,

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cryoprotectant,41 and drug permeation agent.42

Specifically, we map hydrogen bond populations of the S=O and C=O groups in DMSO/water/formamide or dimethylformamide (DMF) ternary mixtures using infrared


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spectroscopy. The sensitivities of S=O37,43 and C=O44-47 stretching vibrations to the local electrostatic environment enabled us to quantify the thermodynamics of hydrogen bonding. Populations were extracted from the S=O and C=O absorption lineshapes, and an atomistic interpretation was achieved by comparing the experimental populations with MD simulations of the same mixtures. Formamide and DMF both increase DMSO–water hydrogen bond populations. Despite differences in polarity, the effects are similar for both amides. In addition, we measured hydrogen bond thermodynamics between all components in the mixtures. The results show that DMSO–water, DMSO–formamide, and water–water interactions are stronger than interactions between water and amides. We selected formamide and DMF as model systems to explore the effects of hydrogen bond donating ability and bulk polarity in ternary mixtures.

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Given their chemical structure and

properties, these amides can be considered minimal models of the protein backbone that have limited chemical complexity and few conformational degrees of freedom. Proteins can change conformation or aggregate in the presence of osmolytes, which may bury or expose polar groups, thus alter the donor/acceptor balance. Conformation-dependent effects, combined with slow structural dynamics, make attempts at establishing relationships between protein structure and solvation shell composition particularly challenging.16,19,35,50-55 These studies are a first step towards bridging the knowledge gap between solvent composition and biomolecular structure, dynamics, and stability. Methods Herein, we provide an outline of experimental procedures and theoretical methods. Details are provided in the Supporting Information.


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FTIR spectroscopy: FTIR measurements were performed with 1 cm-1 resolution using a pair of CaF2 windows. The path length was varied depending on the concentration in order to keep the optical densities within the linear range of the FTIR spectrometer. All chemicals were used as received. Quantum Mechanical calculations: To assign peak frequencies, geometry optimization was performed on putative starting structures using B3LYP/6-31G(d) level, then further optimization and frequency analysis were carried out at the MP2/cc-PVZ level of theory. MD simulations and H-bond analysis: Simulations of DMSO/water binary mixtures, formamide/DMSO/water ternary mixtures, and DMF/DMSO/water ternary mixtures at varying concentrations were carried out with CHARMM General Force-field (CGenFF).56 All simulations were performed using the GROMACS 5.12 package.57 Hydrogen bond populations were computed using a 3.5 Å donor (D) to acceptor (A) distance cutoff, between oxygen atoms of donor and acceptor, and a 30 ° D-H-A angle cutoff. The distance parameter was selected to match the first minimum of the Donor-Acceptor radial distribution function. Results and Discussion Vibrational Line Shapes. Figure 1 shows S=O and C=O stretching band spectra at low (1 mol%), medium (50 mol%), and high DMSO (100 mol%) concentrations. Both vibrational modes are sensitive reporters of their immediate hydrogen bond environments. We have previously decomposed the S=O stretching lineshape into non-hydrogen bonded (0HB), singly hydrogen-bonded (1HB), and doubly hydrogen-bonded (2HB), peaks and have quantified the populations over the entire DMSO/water concentration range.37 Non-hydrogen bonded species include isolated (“Free”) and self-associated DMSO dimers (“Aggregate or Agg”). The S=O and C=O peaks gradually blue shift with increasing DMSO concentrations (see SI Section1,


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Section2, and Figure S1) as hydrogen-bond populations decrease with increasing DMSO concentrations. Figures 1A and S1 show the S=O absorption spectrum within three DMSO concentration regimes in the ternary mixtures. Spectra blue-shift at higher DMSO concentrations as a result of lower S=O H-bond populations. Spectra with formamide or DMF are very similar, except at higher concentrations, which exhibit larger differences. Since the two amides differ in molecular volume and molecular mass, we have chosen to keep the amount of additive constant at 15% w/v to study crowding effects. Formamide and DMF have a different balance of donor/acceptor groups. Formamide can donate two hydrogen bonds through its -NH2 group and accept two hydrogen bonds through its carbonyl. DMF, on the other hand, can only accept two hydrogen bonds. The C=O stretching bands of formamide and DMF serve as additional reporters on the solution environment (Figure 1B, Figure S2). Spectra show blue-shifted lineshapes at higher DMSO concentrations. Formamide and DMF peaks are broad at low concentrations, as the groups are highly solvated. Narrower peaks at higher DMSO concentrations are a result of more uniform 0HB environments. Compared to formamide, DMF shows narrower peaks and smaller spectral shifts, indicating weaker C=O hydrogen bonds. Despite formamide’s ability to donate hydrogen bonds, our electronic structure computations show that hydrogen bonding with the -NH2 group produces only small shifts in the C=O frequencies compared to direct bonding with the C=O. (See SI Section3 and Figure S3). Hydrogen-bond Populations. Quantitative H-bond populations were extracted from the spectra by fitting the lineshapes to individual peaks. The fits were highly constrained based on several criteria described previously.37 In brief, spectra were fit to a combination of six Gaussian


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profiles and populations extracted from the relative peak areas as described in the Supporting Information (Section 4). While the spectral lineshapes of these heterogeneous mixtures are complex and contain several features, including some CH3 bend peaks, we find that a combination of Gaussians reproduces the measured spectra, and their second derivatives, very well, particularly at low and intermediate DMSO concentrations water–water >> formamide–water (Table 1). These studies revealed that formamide–DMSO energies are significantly stronger than formamide–water, suggesting that direct interactions with DMSO can be an important contribution towards increasing the availability of water molecules in the solvent. Our results provide a molecular-level description of crowding effects on solvent environments and may be used as a basis for understanding cryoprotectant toxicity in cells and tissues, since toxicity has been correlated with the number of hydrogen bond donors and acceptors.70 For these reasons, further fundamental studies are required to construct a molecular foundation for understanding the complex biological effects of these small molecules.


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FIGURES.

Figure 1. (A) DMSO infrared absorption spectra in the S=O stretching region. (B) C=O stretching band of formamide (or DMF) in varying DMSO/water mixtures. Concentrationdependent spectra were measured at following concentrations: 15 %w/v formamide (6.5 mol%) or DMF (4.1 mol%) in low (1 mol%), medium (50 mol%) and high (100 mol%) DMSO/D2O mixtures. Final concentrations of DMSO with formamide (or DMF) are 0.93 mol% (0.96 mol%), 43 mol% (45 mol%), and 79 mol% (86 mol%) indicated by red, green, and blue, respectively. Solid and dashed lines indicate DMSO/water solutions with formamide and DMF, respectively.


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Figure 2. Hydrogen bond populations surrounding the S=O group in DMSO/water binary (red), formamide/DMSO/water (blue), and DMF/DMSO/water (black) ternary mixtures across the entire DMSO concentration range. The curves are comparisons between varying mixtures to (A) 2HB, (B) 1HB, (C) DMSO dimers (“Agg”) and (D) “Free”, see also Figure S4. The three observed concentration regimes are labeled “water rich” (0-10 mol%), “crowding” (10-75 mol%) and “DMSO rich” (75-90%). The arrows indicate changes from binary mixtures to ternary mixtures (blue: formamide/DMSO/water, and gray: DMF/DMSO/water).


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Figure 3. Predicted hydrogen bond ensemble populations from MD simulations, plotted as a function of the DMSO mole fraction. Three HB ensemble populations surrounding the S=O group are described in (A) DMSO/water, (B) DMSO/water/formamide, (C) DMSO/water/DMF, and (D) DMSO/water/formamide with DMSO–formamide and DMSO–formamide DMSO– water interactions. DMSO–water interactions are plotted as closed circles, while DMSO– formamide (DMSO – water/formamide) interactions are described as open circles (triangles). Three HB populations are indicated by different colors.


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Figure 4. Analysis of molecular dynamics trajectories: (A) Radial distribution functions surrounding DMSO in the mixtures. Solid and dashed lines indicate DMSO–water and DMSO– amide interactions, respectively. (B) Relative number of molecules in first solvation shell of DMSO. Closed and open circles represent DMSO–water and DMSO–amide interactions.


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Figure 5. (A) Experimental H-bond enthalpies (∆H) and entropies (T∆S at 298.15 K) determined by temperature-dependent FTIR spectroscopy. Error bars represent the fitting uncertainties (Figure S13). *Water–water interactions are from the literature.66 Details of the methods and analyses are provided in the SI Section 6. (B) Average number of H-bonds accepted by formamide (FA) binary mixtures with water, and formamide/water/DMSO ternary mixtures with a constant 17.5 mol% DMSO concentration.


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TABLES. Table 1. Enthalpies and entropies were extracted from temperature-dependent hydrogen bond populations as described in the text. Interaction

Enthalpy

Entropy at 298.15 K

(∆H, kJ/mol)

(T∆S, kJ/mol)

water–DMSO

61.1 ± 13.3

62.6 ± 13.3

formamide–DMSO

31.5 ± 5.40

26.5 ± 5.07

water–water

23.3

11.0

DMSO–DMSO

7.93 ± 0.70

11.5 ± 0.69

formamide–water

4.66 ± 0.65

0.66 ± 0.64

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Author Contributions C.B and K-I. O. designed the research. K-I. O. performed the experiments. C.B. and K-I. O. analyzed the results and wrote the manuscript. Funding Sources We gratefully acknowledge a research grant from the Welch Foundation (F-1891). Notes


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The authors declare no competing financial interest. ACKNOWLEDGMENT This is a Plan II SAWIAGOS Project. Computer simulations were carried out using the Texas Advanced Computing Center (TACC) resources. ASSOCIATED CONTENT Supporting Information. The supporting information includes: 1. Experimental procedures including sample preparation and IR measurements. 2. Lineshape analysis and extraction of Hbond populations from IR spectra. 3. Vibrational frequencies derived from quantum mechanical calculations 4. MD simulation protocols and analysis of results. 5. Additional figures referenced in the text. This information is available free of charge via the Internet at http://pubs.acs.org REFERENCES (1)

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BRIEFS. Crowding and dehydration: Infrared spectra of DMSO and amide mixtures suggest that crowding strengthens DMSO – water hydrogen bonding interactions.

TOC Graphic


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Crowding Stabilizes DMSO â Water Hydrogen-Bonding Interactions

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Crowding Stabilizes DMSO â Water Hydrogen-Bonding Interactions