How First Shell–Second Shell Interactions and ... - ACS Publications

Apr 15, 2018 - Chemical Biology and Molecular Biophysics Program, Taiwan International ... important drug-targets.1 Metal ions play essential roles in...
0 downloads 0 Views 3MB Size
Download PDF
Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

pubs.acs.org/IC

How First Shell−Second Shell Interactions and Metal Substitution Modulate Protein Function Karine Mazmanian,†,‡,§ Todor Dudev,⊥ and Carmay Lim*,†,∥ †

Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 10617, Taiwan § Taiwan and Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan ⊥ Faculty of Chemistry and Pharmacy, Sofia University, Sofia 1164, Bulgaria ∥ Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan

Downloaded via UNIV OF SOUTH DAKOTA on June 16, 2018 at 15:48:39 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: Hydrogen bonds to metal−ligands in proteins play a vital role in biological function. They help to stabilize/ protect the metal complex and enhance metal-binding affinity/ specificity, enzyme−substrate recognition, and enzyme activation. Yet, knowledge of the preferred hydrogen-bonding partners of metal ligands in different metalloproteins is lacking. Using well-calibrated methods, we have determined the preferred hydrogen-bonding partners of Cys− bound to native Zn2+ or xenobiotic Cd2+ in Zn-fingers of varying net charge and solvent accessibility as well as the key factors underlying the observed preference. We show how secondary hydrogen-bonding interactions with metal-bound thiolates might exert a significant impact on Zn2+→Cd2+ substitution and thus protein function. Knowing which Zn-fingers may be vulnerable to structural deformation by Cd2+ is important since this would lead to their inactivation, which might impair cell growth, differentiation, cell-cycle control, and DNA repair.

■

INTRODUCTION Around one-third of all proteins require one or more metal cofactors for proper function and many metalloproteins are important drug-targets.1 Metal ions play essential roles in protein/nucleic acid structure stabilization, enzyme catalysis, cell signaling, muscle contraction, respiration, and photosynthesis.2−5 Their unique properties are also used to create artificial signal cascades,6 synthetic zinc fingers for specific DNA recognition,7 and metal-ligating drug candidates.8 Interactions between the cation and its first/inner-shell ligands generally dictate metal-binding affinity/specificity.2,3,5,9−16 Interactions between the first- and second-shell ligands (especially hydrogen-bonding interactions)2,17−19 can help to stabilize/protect the metal complex or enhance metal binding affinity/ specificity/reactivity.2,18,20−25 They also provide fine-tuning of (i) the metal complex’s redox potential26,27 and (ii) the pKa and orientations of catalytically important metal ligands,2,28−30 thus enhancing enzyme−substrate recognition and activation. Furthermore, they can serve as a signal transduction medium in metal sensors and as transcriptional regulators upon DNA/ RNA binding.31 While the most thermodynamically preferred set of inner-sphere ligands for a given metal ion has been well studied,2,3,5,32−34 that of outer-sphere ligands interacting with the first-shell ligands remains unclear. If and how outer-sphere ligands can tune the preference for a certain cation, thereby affecting protein function is also unclear. Hence, it is of great © XXXX American Chemical Society

interest to elucidate the preferred hydrogen-bonding partners of metal ligands in proteins. Due to the important structural or reactive roles of metalbound cysteines,17,19,35,36 we focus herein on their preferred hydrogen-bonding partners and how they depend on the metal ion. Cysteine, mostly in its deprotonated Cys− state,37,38 can bind a wide range of borderline and “soft” cations such as Cu+/2+, Fe2+/3+, Zn2+, and Cd2+.35 The most common cation ligated by the Cys side chain is Zn2+,2 the second most abundant transition metal ion in organisms.39 Since diamagnetic Zn2+ with a closed-shell [Ar]3d10 electron configuration is spectroscopically silent, it is often substituted by NMR-active Cd2+, which displays similar chemical properties (same oxidation state and filled d10 orbital), to study its environment in proteins.40 However, unlike Zn2+, which is an essential biogenic ion, Cd2+ is carcinogenic and toxic to humans. Cadmium can induce oxidative stress, inhibit DNA repair, tumor suppressor functions and apoptosis, as well as deregulate gene expression and cell cycle control.41−43 A common mechanism underlying cadmium’s multiple toxic effects involves Zn2+ displacement in Zn-enzymes and Zn-finger transcription factors, leading to impaired or no protein function.41,43−46 The different effects of Zn2+ and Cd2+ on Received: April 15, 2018

A

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

of net charge q ranging from −2 to 0, depending on the number of histidine ligands n. All models were built using GaussView 5.064 Calibrating the Geometry Optimization Method. In a recent study,65 nine functionals combined with the Stoll-Preuss SDD basis set66,67 or the larger triple-ζ Pople basis set, 6-311++G(d,p),68−71 were tested for their abilities to reproduce the experimental Zn−L distances in 19 ultra high-resolution X-ray structures containing one or two Zn2+ bound to different numbers and types of protein-like ligands. The M062X/SDD method best reproduced the geometries of the CSD structures with a mean error of 0.036 Å, whereas the M062X/6-311+ +G(d,p) method yielded a slightly larger error of 0.05 Å. Since more flexible and diffuse functions are deemed necessary to properly treat anions and their H-bonding interactions,72−74 which are not included in the SDD basis set, we chose the M062X/6-311++G(d,p) method for geometry optimization of the Zn2+ complexes, and M062X combined with SDD on Cd2+ and 6-311++G(d,p) for the other atoms in optimizing the geometries of the Cd2+ complexes. To test the performance of the M062X/6-311++G(d,p) and M062X/SDD/6-311++G(d,p) methods in reproducing the experimental geometries of Cys-containing Zn2+ and Cd2+ complexes, respectively, we searched for CSD structures containing HBs to Zn2+/ Cd2+-bound sulfur atoms.75 Our search yielded a Zn2+ complex structure with intramolecular HBs to sulfur (CSD ID LOZBIL (Ohydroxydithiobenzoato-S,S′)-bis(o-hydroxydithiobenzoato-S)-zinc), but no Cd2+ complex structure with HBs to S−; hence, we used the CSD structure, CADPEC (bis(toluene-3,4-dithiolato)-cadmium(II)), in which Cd2+ is tetracoordinated to four S−. Table S2 lists the metal− ligand and H-bonding distances in the CSD and fully optimized structures. The optimized structures superimpose well onto the respective X-ray structures (Figure 1) with low root-mean-square deviations (RMSDs) in the metal−ligand distances and angles (Table 1).

protein function are thought to be mediated through cadmium’s stronger interactions with Cys− compared to Zn2+.47,48 However, they could also be mediated by the different hydrogen-bonding partners of Zn2+ vs Cd2+-bound Cys.49 The most frequently found hydrogen-bonding partner of Zn2+-bound thiolates from analyses of protein structures in the Protein Data Bank (PDB)50 is the peptide backbone followed by Lys/Arg (especially in Cys4 and Cys3His sites), Asn/Gln, Tyr, and Ser/Thr side chains.2,17,51 Consistent with these findings, calculations show that the second-shell peptide backbone and Lys+/Arg+ side chain stabilize Cys-rich Zn2+ sites.37 Hydrogen bonds (HBs) to Zn2+-bound thiolates can affect reactivity: altering a single HB to the Zn2+-bound thiolate could significantly decrease enzymatic activity.52 Furthermore, backbone NH···S hydrogen bonds can suppress the alkylation rate of all Zn2+-bound thiolates,36,53−55 Compared to Zn2+, Cd2+ interacts differently with the Cys thiolates: Cysteines bound to Cd2+ show stronger HBs with the backbone than those bound to Zn2+ in disulforedoxin56 and metallothioneins.57 Since Cd2+ is a weaker Lewis acid than Zn2+, it yields a more nucleophilic thiolate than Zn2+-bound Cys−.58 However, it is not known if the different effects of Zn2+ and Cd2+ extend to different preferences for hydrogen-bonding partners of the metal-bound Cys−, which may contribute to the destabilization of functional sites upon substitution of Zn2+ and Cd2+.59−62 In this paper, we aim to address the following intriguing questions: 1. Is there a preference among the amino acid (aa) side chains relative to the peptide backbone to form HBs to metal-bound Cys−, as found for free thiolates?63 2. If so, how does this preference depend on (a) the ligand composition, (b) the various protein environments, and (c) the nature of the cation; e.g., Zn2+ vs Cd2+? To address these questions, we have assessed the competition between the backbone and various aa side chains to form HBs with metal-bound Cys− in various Zn2+ and Cd2+ complexes. The outcome of this competition was assessed by the free energy (ΔGε) for displacing the peptide backbone that is hydrogen-bonded to a metal-bound Cys− with an aa side chain X in a protein environment characterized by an effective dielectric constant ε.63

Figure 1. Overlay of fully optimized geometries (cyan) with the respective experimental structure (green). The Zn2+ complex (LOZBIL) was optimized using M06-2X/6-311++G(d,p), whereas the Cd2+ complex (CADPEC) was optimized using M062X/SDD/6311++G(d,p). The ligand-to-metal distances are indicated by solid lines, whereas H-bonding interactions are indicated by dashed lines.

Table 1. RMSDs of Distances and Angles between the Optimized and X-ray Structures

[M−Cys3 − nHisnCys‐‐‐Bkbn] + X → [M−Cys3 − nHisnCys‐‐‐X] + Bkbn

RMSD

(1) cation

where M = Zn2+ or Cd2+, and n = 0, 1, or 2. A negative ΔGε implies that the metal-ligating Cys− prefers to interact with the aa side chain X rather than the peptide backbone in an environment characterized by ε. The results not only reveal the preferred hydrogen-bonding partners of Zn2+- and Cd2+-bound thiolates, but also provide physical bases for the observed preference. They also provide a rationale for some of cadmium’s toxic effects and guide the use of Cd2+ as a spectroscopic probe for spectroscopically silent Zn2+.

■

CSD ID

distance (Å)

Zn

LOZBIL

0.06 (S−Zn) 0.03 (S−O) −0.14 (S−H)

0.76 (S−Zn−S) 2.11 (S−H−O)

Cd2+

CADPEC

0.08 (S−Cd)

−0.03 (S−Cd−S)

2+

angle (deg)

Thus, the M062X/6-311++G(d,p) and M062X/SDD/6-311++G(d,p) methods were used to compute the geometries and the vibrational frequencies of the Zn2+ and Cd2+ complexes, respectively, using the Gaussian 0976 program, version c. The metal complexes were constructed to minimize the interaction of the second-shell HB donor with non-Cys ligands. No imaginary frequencies were found in any of the fully optimized structures. In the fully optimized structure of the [Zn/Cd:Cys4]2−:His+ complex, a proton from protonated His+ was transferred to Cys−. However, this was not observed in the respective

METHODS

Models Used. The metal-ligating aa side chains and hydrogenbonding partners in their neutral or ionized form at physiological pH were modeled by the model compounds in Table S1. Tetracoordinated (Zn/Cd)2+ complexes were modeled as [(Zn/Cd) Cys4‑nHisn]q B

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

components of the total interaction energy Einter between the metal complex and the H-bonding donor aa (treated as monomers 1 and 2) were obtained using the Localized Molecular Orbital Energy Decomposition Analysis (LMO-EDA) scheme:93

conductor-like polarizable continuum model (CPCM)-optimized structure at ε = 4. Hence, the N−H distance in His+ was constrained to the value obtained using CPCM with ε = 4, and the resulting constrained-optimized structure was used to compute the ΔGε in eq 1. Calibrating Gas-Phase Free Energy Calculations. The vibrational frequencies were scaled by an empirical factor of 0.97977 and used to compute the change in the thermal energy including zeropoint energy, ΔEth, and entropy ΔS for eq 1. The differences in the electronic energy ΔEel, ΔEth, ΔPV (work term), and ΔS between the products and reactants in eq 1 were used to compute the gas-phase free energy ΔG1 at a temperature T of 298.15 K using the Gaussian 09 program according to

ΔG1 = ΔEel + ΔEth + ΔPV − T ΔS

E inter = E ES + E EX + E REF + E POL + E DISP

where EES is the electrostatic interaction of the occupied orbitals of the monomers, EEX is the energy of the exchange of electrons between the monomers, EREP is the short-range repulsion of the overlapping electron distributions of the monomers, EPOL is the distortion energy of the electron distributions of monomers, and EDISP is an attractive dispersion energy. The calculations were performed using Gamess version R1 (Aug 2016)94 based on the fully optimized structures. Since the 6-311++G(d,p) is not available for Zn2+ in Gamess and the LMOEDA is not sensitive to the basis set,93 we used the B98 functional in conjunction with the SDD basis set for both cations and the 6-311+ +G(2d,2p) basis set for N, C, O, S, H.95

(2)

Single-point energy calculations of the HB complexes were performed using the B98 functional in conjunction with the 6-311++G(2d,2p) basis set for all atoms, except Cd2+, which employed the SDD basis set. The B98/6-311++G(2d,2p) method was chosen because it performed well in computing the energies of hydrogen-bonding and weak noncovalent interactions.78,79 It can also reproduce the deprotonation free energy of CH3SH to within 0.2 kcal/mol.63 Basis set superposition error was estimated using the counterpoise method and added to ΔG1 to yield the final energies reported herein. Calibrating Solvation Free Energy Calculations. The solvation free energy ΔGsolvε was estimated by solving Poisson’s equation using finite difference methods80,81 with the MEAD (Macroscopic Electrostatics with Atomic Detail) program,82 as described in previous works.83 The continuum dielectric calculations employed the fully optimized geometries and natural bond orbital atomic charges as well as effective solute radii Reff (Table S3) that have been adjusted to reproduce the pKa and/or experimental ΔGsolv80 solvation free energies of the compounds in Table 2. Energy Decomposition Analyses. To obtain insight into the hydrogen-bonding interactions in the various systems,90−92 the

■

RESULTS The aa side chains interacting with metal-bound Cys− were divided into three groups: positively charged (Lys+, Arg+, His+), aromatic (His0, Tyr, Trp), and small polar (Ser/Thr, Cys0, and Asn/Gln) residues. We assessed which of these aa side chains are preferred over the peptide backbone in interacting with metal-bound Cys− in the various Zn2+ sites shown in Figure 2. In interpreting the results, we focused on the trends in the changes of free energy for displacing the peptide backbone with an aa side chain X rather than their absolute values. HBs to Charged Residues Are Preferred over Backbone in Buried Zn2+ Sites. Without the protein matrix, positively charged aa residues are strongly preferred over the backbone amide with Lys+ being the most preferred, regardless of the net charge/composition of the metal complex (highly negative ΔG1 in Figure 3). Lys+ is followed by His+ in the fully optimized [Zn:Cys3His]− and [Zn:Cys2His2]0 complexes (note that the [Zn:Cys4]2−:His+ complex was constrained optimized to prevent transfer of a proton from His+ to Cys−, see Methods). The observed preference correlates with the measured gas-phase basicities, which increase as Lys < His < Arg (Table 3). Hence, Lys+ with the lowest gas-phase basicity is the preferred H-bonding partner of metal-bound Cys− among the charged residues. The preference for positively charged aa residues over the backbone amide increased with increasing net negative charge of the Zn2+ site: For example, the ΔG1 for displacing an outershell backbone with Lys+ decreased from −50 kcal/mol in neutral [Zn:Cys2His2]0 to −107 kcal/mol in monoanionic [Zn:Cys3His]− and further to −167 kcal/mol in dianionic [Zn:Cys4]2−. This is mainly due to increasingly favorable electrostatic interaction energy with the positively charged aa residue with increasing net negative charge of the Zn2+ complex, as shown by the energy decomposition analysis of the outer shell---inner shell interaction energy (Figure S1). How would solvation by a protein matrix change the preferred H-bonding partner of metal-bound Cys−? A positively charged residue is better solvated than a neutral backbone. Furthermore, it reduces the net charge of anionic Zn2+ sites, which become less well-solvated than the respective backbone hydrogen-bonded sites. Hence, increasing solvent-exposure of the Zn2+ site weakened the preference for the charged residues relative to the neutral peptide backbone, the attenuation magnifying with increasing negative charge of the Zn2+ site such that the preferred hydrogen-bonding partner of the metalligating thiolates, Lys+ > His+ > Arg+ > backbone, is maintained

Table 2. Computed and Experimentala Solvation Free Energies of Acids, ΔGsolv80(AH), and Conjugate Bases, ΔGsolv80(A), and Respective pKa Values in Water ΔGsolv80 (kcal/mol) molecule AH

AH

A

pKa

imidazolium, (CH)3N(NH) phenol, C6H6O methanethiol, CH3SH methylammonium, CH3NH3+ methylguanidinium, C2H8N3+ methanol, CH3OH N-methylacetamide, CH3CONHCH3 acetamide, CH3CONH2 3-methylindole, C9H10N

−64.7

−9.9 (−10.2c) −69.1

7.11 (7.05) 10.07 (10.0) 10.8 (10.3) 10.8 (10.6) 13.6 (13.4) 15.8 (15.5) −

−6.4 (−6.6b) −0.9 (−1.2b) −75.3 −58.8 −5.0 (−5.1b) −9.7 (−10.0e) −9.6 (−9.7f) −5.9 (−5.9g)

−71.8 −4.4 (−4.6b) −10.9 (−11.2d) −93.4 − −

−

−

−

(3)

a

Experimental values, where available, are in parentheses; the superscript “80” corresponds to the dielectric constant of water. The pKa values were computed using the experimental hydration free energy of the proton for a standard state of 1 M (−265.9 kcal/mol).84 b From Kelly, 2005.85 cFrom Lim et al., 1991.81 dFrom Vorobyov et al., 2008.86 eFrom Wolfenden, 1978.87 fFrom Wolfenden, 1981.88 gFrom Sitkoff et al., 1994.89 C

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

Figure 2. Fully optimized structures of [Zn:Cys4‑nHisn]q---Bkb0 complexes. HBs are indicated as dashed lines; Zn2+ is in silver, S in yellow, O in red, N in blue, C in green, and H in white.

Figure 3. Free energies for eq 1 derived from the M062X/6-311++G(d,p)-optimized structures of [Zn:Cys4‑nHisn]q:X+ complexes. All structures were fully optimized except for the [Zn:Cys4]2−:His+ complex, where the N−H distance in His+ was constrained to the value obtained using CPCM with ε = 4 to prevent proton transfer from His+ to Cys−. HBs are indicated by dashed lines. Atom colors as in Figure 2.

Table 3. Experimental Dipole Moments μ, Gas-Phase Basicities ΔGB°, and pKa Values of aa Side Chain Models residue +

Lys His+ Arg+ His0 Tyr Trp Cys backbone Ser/Thr

model compounda methylammonium imidazolium methylguanidinium imidazole phenol indole methanethiol N-methylacetamide methanol

no. of HBs

μ (Debye)

2 1 4 1 1 1 1 1 1

− − − 3.60i 1.22f 1.96g 1.52f 3.71h 1.70f

ΔGB° (kcal/mol) 206.6 ± 217.7 ± 226.9c 342.6 ± 342.9 ± 344.1 ± 351.3 ± 354.5 ± 374.8 ±

b

0.5 0.5b 0.4d 1.4b 2.0b 0.4e 2.0b 0.7b

pKa 10.6k 7.1l 13.4m − 10.0j − 10.3j − 15.5j

a The gas-phase basicity of the model compound BH is defined as the negative of the gas-phase free energy change for the B + H+ →BH. bFrom Linstrom and Mallard, 2003.96 cFor the arginine side-chain model (N-methylguanidine), no experimental value was found. Hunter and Lias report ΔG° = 226.9 kcal/mol for guanidine.97 dFrom Gianola et al., 2005.98 eFrom Ervin et al., 2015.99 fFrom Johnson, 2016.100 gFrom Kang et al., 2005.101 h From Cheam and Krimm, 1985.102 iFrom Christen et al., 1982.103 jFrom Kelly et al., 2005.85 kFrom Daley and Daley, 2013.104 lFrom Walba and Isensee, 1961.105 mFrom Rynkiewicz and Seaton, 1996.106

in neutral Zn2+ sites even if they are partially solvent exposed and in anionic Zn2+ sites only if they are buried. In monoanionic [Zn:Cys3His]− sites that are partially exposed, only Lys+ is still preferred over the backbone. HBs to Tyr and His Are Preferred over Backbone. In the absence of the protein environment, Zn2+-bound thiolates

prefer aromatic HB donors over the backbone amide, whose gas-basicity is less favorable than that of His0/Tyr/Trp (Table 3). Since neutral aromatic residues do not alter the net charge of the Zn2+ site, solvation effects are much weaker than those observed for charged residues in the outer-shell. Thus, irrespective of the solvent accessibility and net charge of the D

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

Figure 4. Free energies for eq 1 derived from the optimized structures of [Zn:Cys4‑nHisn]q:Xarom complexes. HBs are indicated as dashed lines. Atom colors as in Figure 2.

Figure 5. Free energies for eq 1 derived from the M062X/6-311++G(d,p)-optimized structures of [Zn:Cys4‑nHisn]q:X0 complexes. The HBs are indicated as dashed lines. Atom colors as in Figure 2.

= 5.7 for Ser/Thr and ΔG1 = 8.1 for Cys, Figure 5). Since the dipole-charge interactions attenuate with diminishing net charge Q of the metal complex, the unfavorable ΔG1 free energy for substituting the backbone amide with Ser/Thr/Cys decreased with decreasing Q; e.g., the ΔG1 for substituting the backbone amide with Cys decreased from 8.1 to 4.5 to 0.9 kcal/ mol when Q decreased from −2 to −1 to 0. Solvent exposure of the Zn2+ site further decreased the Bkbn → Ser/Thr/Cys free energy. Consequently, there is no dislike/preference for small polar HB donors (Cys and Ser/Thr) over the peptide backbone in forming HBs with the Zn2+-bound thiolates.

Zn2+ site, Tyr and His0 are preferred over the backbone amide as HB donors to Zn2+-bound thiolates, whereas the bulky Trp0 exhibits no significant preference over the backbone in proteins (Figure 4). No H-Bonding Preference for Small Polar Residues over the Backbone. The backbone has a larger dipole moment than Ser/Thr/Cys (3.7 vs ∼1.6 D, Table 3) and forms more favorable dipole−charge interactions. Thus, in an isolated dianionic [Zn:Cys4]2− complex where electrostatic interactions prevail, the Zn-bound thiolates prefer to form HBs with the backbone amide rather than the Ser/Thr/Cys side chain (ΔG1 E

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

Figure 6. Optimized structures of [Cd:Cys4‑nHisn]q hydrogen-bonded complexes superimposed upon those of [Zn:Cys4‑nHisn]q counterparts. In the [Cd:Cys4‑nHisn]q complexes, Cd2+ is depicted as a yellow sphere; other atom colors as in Figure 2 caption. The respective [Zn:Cys4‑nHisn]q hydrogen-bonded complexes are shown in transparent silver.

dianionic ones. For example, the ΔG1 for displacing the outershell backbone with Arg+ in [Cd:Cys2His2]0 sites (−33.0 kcal/ mol) is more favorable than that in [Zn:Cys2His2]0 sites (ΔG1 = −28.9 kcal/mol). Another consequence of the size difference between Zn2+ and Cd2+ is that the larger Cd2+ forms bulkier complexes than Zn2+ and exhibits weaker solvation effects. Hence, increasing solvent-exposure of the Cd2+ site does not weaken the preference for the charged residues over the backbone amide as much as increasing solvent-exposure of the respective Zn2+ site: For sites that preserve their geometries upon Zn2+→Cd2+ substitution, the ΔGε (ε > 4) free energies for the bulkier Cd2+ complexes are generally more negative or less positive than those for the Zn2+ counterparts. Consequently, Cd2+-bound thiolates in non-deformed complexes generally showed stronger preference for aa side chains over the backbone than the Zn2+-bound thiolates in both buried and exposed sites. The combined geometrical changes and size effects resulting from the Zn2+→Cd2+ substitution produced some interesting differences in the preferred hydrogen-bonding partner of metalbound Cys−. Relative to the peptide backbone, the bulkier Trp and Cys0 side chains prefer to donate HBs to neutral [Cd:Cys2His2]0 and monoanionic [Cd:Cys3His]− complexes, respectively, but there is no particular preference for the more compact Zn2+ complexes.

Differences between Cd2+ and Zn2+ Complexes. Would replacing the native Zn2+ with “toxic” Cd2+ in the metal− thiolate complexes change the coordination geometries and the preferred HB partners for the metal-ligating thiolates? To address this question, we replaced Zn2+ in the optimized complexes with Cd2+, and the resulting Cd2+ complex was allowed to optimize freely. The extent to which the structure was deformed upon metal substitution was measured by the RMSDs of all atoms in the Zn2+ and Cd2+ complexes. Upon replacing Zn2+ with the “alien” Cd2+, Cys2His2 sites lined by the peptide backbone or small neutral aa side chains such as Asn/Gln, His0, Ser/Thr, and Tyr in the outer shell (Figure 6) underwent larger conformational changes (RMSD > 1 Å) than the respective bulkier sites with three or four Cys− (see Figure S2−S4). In these sites, Cd2+ recruited the outershell Asn/Gln/Ser/Thr side chain to its inner-shell and became pentacoordinated, although these “new” ligands can retain their HBs to metal-bound Cys−. Interestingly, the backbone O came closer to Cd2+ (3.3 Å) than to Zn2+ (4.01 Å) but did not directly bind Cd2+, unlike the Asn/Gln side chain O, due likely to steric constraints. Likewise, the Tyr hydroxyl O also came closer to Cd2+ than to Zn2+ but did not directly bind Cd2+. Although His0 remained in the outer-shell forming a HB with Cd2+-bound Cys−, it formed a second nonlinear HB with a Cd2+-bound His, thus distorting the native metal coordination geometry (Figure 6). For the same coordination number, Zn2+ and Cd2+ differ mainly in size, Cd2+ being larger than Zn2+: the ionic radii Rion of tetracoordinated Cd2+ and Zn2+ are 0.78 and 0.60 Å, respectively.107 Since the mean metal−ligand distance increases with increasing Rion,108 Cd2+ forms longer bonds than Zn2+, resulting in differences in the enthalpic and entropic contributions to the ΔGε for eq 1. Compared to Zn2+, the longer bonds to Cd2+ result in less ligand→Cd2+ charge transfer, leaving more negative charge on the Cd2+-bound thiolates to gain stronger hydrogen-bonding interactions. Furthermore, an entropic advantage may be gained in displacing the hydrogen-bonded backbone with an aa side chain in the “looser” Cd2+ complex than the more compact Zn2+-counterpart. Indeed, the gas-phase ΔG1 free energies are more negative for sites that exhibit insignificant conformational change upon Zn2+→Cd2+ substitution, especially monoanionic/ neutral metal sites where electrostatic effects are weaker than

■

DISCUSSION Single-nucleotide polymorphisms involving second-shell residues of metal-binding sites can lead to disease phenotypes, underscoring the importance of HBs to metal−ligands in proteins.1,109,110 Knowing the principles governing the preferred H-bonding partners of metal ligands would help to elucidate how the protein matrix controls the metal-binding site,17 and guide the biomimetic design of small molecules, functional metalloproteins,111 drug design,112 or biosensors.113 This is underscored by recent trends in metalloprotein design, focusing on modifying the non-covalent second-shell interactions to fine-tune the metal-binding affinity; e.g., in attempting to inhibit an enzymatic Zn2+-binding site with thiol-containing compounds, HBs to Zn2+-bound thiolates were found to be the most important factor controlling the successful binding of thiolates to Zn2+.112 F

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

Cd2+ to protein scaffolds such as coiled-coil peptides by manipulating first shell---second shell interactions.117

Despite the widely acknowledged importance of backbone amide HBs to Zn2+-bound thiolates, aa HB donors have been overlooked. Herein, we have revealed those aa side chains that are preferred over the peptide backbone in forming HBs to metal-bound Cys− as well as the key factors underlying their preference: Relative to the peptide backbone, aa side chains with significantly lower gas-basicities; viz., Lys+, His+, Arg+, and to a lesser extent non-bulky, aromatic Tyr and His prefer to form HBs to solvent-shielded Zn 2+ -bound Cys − . The preference for these aa side chains over the peptide backbone attenuates with diminishing net charge of the metal site as well as increasing solvent accessibility of the metal site for the charged aa residues (but not neutral Tyr and His). Upon Zn2+→Cd2+ substitution, the charge preservation but size difference of the two cations yielded similarities and differences, respectively, in the preferred hydrogen-bonding partner of metal-bound Cys−: As Zn2+ and Cd2+ are both dicationic, positively charged side chains are preferred over the backbone in hydrogen-bonding to the metal-bound Cys−. But since Cd2+ is larger than Zn2+ for the same CN, its bound thiolate in neutral [Cd:Cys2His2]0 and monoanionic [Cd:Cys3His]− complexes prefer the bulkier Trp0 and Cys0 side chains over the peptide backbone, respectively. Thus, the H-bonding partners of metal-bound thiolate are similar for Zn2+ and Cd2+ in Cys4 sites where strong electrostatic interactions prevail, but they differ with decreasing charge of the metal site. Notably, small Asn/Gln and Ser/Thr side chains in the outer shell of [Zn:Cys2His2]0 sites move to the inner shell upon Zn2+→Cd2+ substitution. Biological Implications. Our findings suggest that Zn2+→ Cd2+ substitution might not preserve the structural integrity of flexible classical [Zn:Cys2His2]0 fingers lined by Asn/Gln/Ser/ Thr side chains in the outer shell that could coordinate Cd2+. Consistent with our findings, Ser77 forms a HB with Zn2+bound Cys80 (O---S ≈ 4.1 Å) in the NMR structure of the TFIIIA classical Zn-finger (PDB ID: 1TF3)114 and Zn2+→Cd2+ substitution has been shown to disrupt DNA binding.115 Also consistent with our findings, comparison of high-resolution crystal structures of a Cd2+ complex and its Zn analogue containing two S and two N ligands bound to the metal ion shows tetrahedral geometry for the Zn2+ complex, but a considerably distorted tetrahedron for the Cd2+ complex, as a second-shell oxygen came closer to Cd2+ (3.23 Å) than to Zn2+ (4.03 Å).116 In contrast to classical Zn-fingers with neutral, flexible Zn2+ sites, proteins with anionic Zn2+ sites that form strong interactions with cationic side chains can be studied using Zn2+→Cd2+ substitution, as the geometries and first shell--second shell interactions are similar for both metal complexes. In accordance with our findings, NMR structures of disulforedoxin with Zn2+ and Cd2+ bound to four Cys show that the backbone amides retain their HBs to the thiolates upon Zn2+→Cd2+ substitution.56 Furthermore, different spectroscopic methods show that Cd2+ can bind to all four Cys− in the DNA-binding domain of Xeroderma pegmentosum A (XPA) protein with no major structural distortion.49 In summary, Cd2+ is more likely to exert toxic effects in neutral, flexible Zn2+ sites lined by small neutral aa side chains than in charged, rigid Zn2+ sites, as it could distort the native protein structure and thereby alter/abolish the protein function. As a result, we do not recommend using Cd2+ as a spectroscopic probe for Zn2+ in such neutral, flexible sites. Our findings may also help to create specific binding of Zn2+/

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.8b01029. Table S1, compounds modeling amino acid side chains and peptide backbone groups; Table S2, metal−ligand and hydrogen-bonding distances in X-ray and optimized structures; Table S3, effective solute radii Reff of the model compounds; Figure S1, energy decomposition analyses of the interaction energy between arginine and various Zn sites relative to that between the backbone and the respective Zn sites; and Figures S2−S4, optimized structures of [Cd:Cys4‑nHisn]q hydrogenbonded complexes superimposed upon those of [Zn:Cys4‑nHisn]q counterparts (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Todor Dudev: 0000-0002-8186-2141 Carmay Lim: 0000-0001-9077-7769 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by research grants from the Ministry of Science & Technology (MOST 106-14) and Academia Sinica, Taiwan.

■

REFERENCES

(1) Levy, R.; Sobolev, V.; Edelman, M. First- and second-shell metal binding residues in human proteins are disproportionately associated with disease-related SNPs. Hum. Mutat. 2011, 32, 1309−18. (2) Dudev, T.; Lin, Y. L.; Dudev, M.; Lim, C. First-second shell interactions in metal binding sites in proteins: A PDB survey and DFT/CDM calculations. J. Am. Chem. Soc. 2003, 125, 3168−3180. (3) Dudev, T.; Lim, C. Metal binding and selectivity in metalloproteins: Insights from computational studies. Annu. Rev. Biophys. 2008, 37, 97−116. (4) Que, E. L.; Domaille, D. W.; Chang, C. J. Metals in neurobiology: Probing their chemistry and biology with molecular imaging. Chem. Rev. 2008, 108, 1517−1549. (5) Dudev, T.; Lim, C. Competition among metal ions for protein binding sites: Determinants of metal ion selectivity in proteins. Chem. Rev. 2014, 114, 538−556. (6) Graf, N.; Krämer, R. Enzymatic amplification in a bioinspired, autonomous signal cascade. Chem. Commun. 2006, 13, 4375−4376. (7) Gersbach, C. A.; Gaj, T.; Barbas, C. F. r. Synthetic zinc finger proteins: the advent of targeted gene regulation and genome modification technologies. Acc. Chem. Res. 2014, 47, 2309−2318. (8) Mjos, K. D.; Orvig, C. Metallodrugs in Medicinal Inorganic Chemistry. Chem. Rev. 2014, 114, 4540−63. (9) Coleman, J. E. Zn proteins: Enzymes, storage proteins, transcription factors and replication proteins. Annu. Rev. Biochem. 1992, 61, 897−946. (10) Black, C. B.; Cowan, J. A. Quantitative evaluation of electrostatic and hydrogen-bonding contributions to metal cofactor binding to nucleic acids. J. Am. Chem. Soc. 1994, 116, 1174−1178.

G

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry (11) Falke, J. J.; Drake, S. K.; Hazard, A. L.; Peersen, O. B. Molecular tuning of ion binding to calcium signaling proteins. Q. Rev. Biophys. 1994, 27, 219−290. (12) Jernigan, R.; Raghunathan, G.; Bahar, I. Characterization of interactions and metal ion binding sites in proteins. Curr. Opin. Struct. Biol. 1994, 4, 256−263. (13) Lippard, S. J. Metals in Medicine. In Bioinorganic Chemistry; Bertini, I., Gray, H. B., Lippard, S. J., Valentine, J. S., Eds.; University Science Books: Mill Valley, CA, 1994; pp 505−584. (14) Cowan, J. A. Biological Chemistry of Magnesium; VCH: New York, 1995. (15) Dismukes, G. C. Manganese Enzymes with Binuclear Active Sites. Chem. Rev. 1996, 96, 2909−2926. (16) Lipscomb, W. N.; Strater, N. Recent Advances in Zinc Enzymology. Chem. Rev. 1996, 96, 2375−2434. (17) Maynard, A. T.; Covell, D. G. Reactivity of Zinc Finger Cores: Analysis of Protein Packing and Electrostatic Screening. J. Am. Chem. Soc. 2001, 123, 1047−1058. (18) Lin, Y.; Lee, Y.; Lim, C. Differential effects of the Zn-His-Bkb vs Zn-His-[Asp/Glu] triad on Zn-core stability and reactivity. J. Am. Chem. Soc. 2005, 127, 11336−11347. (19) Picot, D.; Ohanessian, G.; Frison, G. The Alkylation Mechanism of Zinc-Bound Thiolates Depends upon the Zinc Ligands. Inorg. Chem. 2008, 47, 8167−8178. (20) Vipond, I. B.; Moon, B.-J.; Halford, S. E. An isoleucine to leucine mutation that switches the cofactor requirement of the EcoRV restriction endonuclease from magnesium to manganese. Biochemistry 1996, 35, 1712−1721. (21) Mertz, P.; Yu, L.; Sikkink, R.; Rusnak, F. Kinetic and spectroscopic analyses of mutants of a conserved histidine in the metallophosphatases calcineurin and l protein phosphatase. J. Biol. Chem. 1997, 272, 21296−21302. (22) He, Q.-Y.; Mason, A. B.; Woodworth, R. C.; Tam, B. M.; MacGillivray, R. T. A.; Grady, J. K.; Chasteen, N. D. Mutations at nonliganding residues Tyr-85 and Glu-83 in the N-lobe of human serum transferrin. J. Biol. Chem. 1998, 273, 17018−17024. (23) Marino, S. F.; Regan, L. Secondary ligands enhance affinity at a designed metal-binding site. Chem. Biol. 1999, 6, 649−655. (24) Cox, E. H.; McLendon, G. L. Zinc-dependent protein folding. Curr. Opin. Chem. Biol. 2000, 4, 162−165. (25) DiTusa, C. A.; Christensen, T.; McCall, K. A.; Fierke, C. A.; Toone, E. J. Thermodynamics of metal ion binding. 1. Metal ion binding by wild-type carbonic anhydrase. Biochemistry 2001, 40, 5338−5344. (26) Brammer, L. Metals and hydrogen bonds. Dalton Trans. 2003, 3145−3157. (27) Hadt, R. G.; Sun, N.; Marshall, N. M.; Hodgson, K. O.; Hedman, B.; Lu, Y.; Solomon, E. I. Spectroscopic and DFT studies of second-sphere variants of the type 1 copper site in azurin: covalent and nonlocal electrostatic contributions to reduction potentials. J. Am. Chem. Soc. 2012, 134, 16701−16716. (28) Kiefer, L. L.; Paterno, S. A.; Fierke, C. A. Hydrogen bond network in the metal binding site of carbonic anhydrase enhances zinc affinity and catalytic efficiency. J. Am. Chem. Soc. 1995, 117, 6831− 6837. (29) El Yazal, J.; Roe, R. R.; Pang, Y.-P. Zinc’s effect on proton transfer between imidazole and acetate predicted by ab initio calculations. J. Phys. Chem. B 2000, 104, 6662−6667. (30) Dudev, T.; Lim, C. Tetrahedral vs. octahedral zinc complexes with ligands of biological interest: a DFT/CDM study. J. Am. Chem. Soc. 2000, 122, 11146−11153. (31) Maret, W.; Li, Y. Coordination Dynamics of Zinc in Proteins. Chem. Rev. 2009, 109, 4682−4707. (32) Dudev, T.; Lim, C. Bidentate vs. monodentate carboxylate coordination modes in magnesium and calcium proteins: What are the basic principles? J. Phys. Chem. B 2004, 108, 4546−4557. (33) Dudev, T.; Lim, C. All-electron calculations of the nucleation structures in metal−induced zinc-finger folding: Role of the peptide backbone. J. Am. Chem. Soc. 2007, 129, 12497−12504.

(34) Zou, R.; Wang, Q.; Wu, J.; Wu, J.; Schmuck, C.; Tian, H. Peptide self-assembly triggered by metal ions. Chem. Soc. Rev. 2015, 44, 5200−5219. (35) Giles, N. M.; Watts, A. B.; Giles, G. I.; Fry, F. H.; Littlechild, J. A.; Jacob, C. Metal and redox modulation of cysteine protein function. Chem. Biol. 2003, 10, 677−693. (36) Lee, Y.-M.; Lim, C. Factors controlling the reactivity of zinc finger cores. J. Am. Chem. Soc. 2011, 133, 8691−8703. (37) Dudev, T.; Lim, C. Factors governing the protonation state of cysteines in proteins: An Ab Initio/CDM study. J. Am. Chem. Soc. 2002, 124, 6759−6766. (38) Lin, Y.; Lim, C. Factors governing the protonation state of Znbound histidine in proteins: A DFT/CDM study. J. Am. Chem. Soc. 2004, 126, 2602−2612. (39) Sousa, S. F.; Lopes, A. B.; Fernandes, P. A.; Ramos, M. J. The Zinc proteome: a tale of stability and functionality. Dalton Trans. 2009, 7946−7956. (40) Malgieri, G.; Grasso, G. The clearance of misfolded proteins in neurodegenerative diseases by zinc metalloproteases: An inorganic perspective. Coord. Chem. Rev. 2014, 260, 139−155. (41) Quintal, S. M.; dePaula, Q. A.; Farrell, N. P. Zinc finger proteins as templates for metal ion exchange and ligand reactivity. Chemical and biological consequences. Metallomics 2011, 3, 121−139. (42) Hartwig, A. Mechanisms in cadmium-induced carcinogenicity: recent insights. BioMetals 2010, 23, 951−960. (43) Wätjen, W.; Benters, J.; Haase, H.; Schwede, F.; Jastorff, B.; Beyersmann, D. Zn2+ and Cd2+ increase the cyclic GMP level in PC12 cells by inhibition of the cyclic nucleotide phosphodiesterase. Toxicology 2001, 157, 167−175. (44) Petering, D. H.; Huang, M.; Moteki, S.; Shaw, C. F., III. Cadmium and lead interactions with transcription factor IIIA from Xenopus laevis: a model for zinc finger protein reactions with toxic metal ions and metallothionein. Mar. Environ. Res. 2000, 50, 89−92. (45) Beyersmann, D.; Hartwig, A. Carcinogenic metal compounds: recent insight into molecular and cellular mechanisms. Arch. Toxicol. 2008, 82, 493−512. (46) Malgieri, G.; Zaccaro, L.; Leone, M.; Bucci, E.; Esposito, S.; Baglivo, I.; Del Gatto, A.; Russo, L.; Scandurra, R.; Pedone, P. V.; Fattorusso, R.; Isernia, C. Zinc to cadmium replacement in the A. thaliana SUPERMAN Cys2His2 zinc finger induces structural rearrangements of typical DNA base determinant positions. Biopolymers 2011, 95, 801−810. (47) Krizek, B. A.; Merkle, D. L.; Berg, J. M. Ligand Variation and Metal Ion Binding Specificity in Zinc Finger Peptides. Inorg. Chem. 1993, 32, 937−940. (48) Kepp, K. P. Bioinorganic Chemistry of Alzheimer’s Disease. Chem. Rev. 2012, 112, 5193−5239. (49) Hartwig, A. Zinc finger proteins as potential targets for toxic metal ions: differential effects on structure and function. Antioxid. Redox Signaling 2001, 3, 625−634. (50) Berman, H. M.; Battistuz, T.; Bhat, T. N.; Bluhm, W. F.; Bourne, P. E.; Burkhardt, K.; Feng, Z.; Gilliland, G. L.; Iype, L.; Jain, S.; Fagan, P.; Marvin, J.; Padilla, D.; Ravichandran, V.; Schneider, B.; Thanki, N.; Weissig, H.; Westbrook, J. D.; Zardecki, C. The Protein Data Bank. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2002, 58, 899− 907. (51) Karlin, S.; Zhu, Z.-Y. Classification of mononuclear zinc metal sites in protein structures. Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 14231−14236. (52) Teh, A. H.; Kimura, M.; Yamamoto, M.; Tanaka, N.; Yamaguchi, I.; Kumasaka, T. The 1.48 A resolution crystal structure of the homotetrameric cytidine deaminase from mouse. Biochemistry 2006, 45, 7825−7833. (53) Smith, J. N.; Shirin, Z.; Carrano, C. J. Control of thiolate nucleophilicity and specificity in zinc metalloproteins by hydrogen bonding: lessons from model compound studies. J. Am. Chem. Soc. 2003, 125, 868−869. (54) Smith, J. N.; Hoffman, J. T.; Shirin, Z.; Carrano, C. J. HBonding Interactions and Control of Thiolate Nucleophilicity and H

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Specificity in Model Complexes of Zinc Metalloproteins. Inorg. Chem. 2005, 44, 2012−2017. (55) Ibrahim, M. M. The influence of hydrogen bonding on the rate of thiolate alkylation in tripod-zinc thiolate complexes. Inorg. Chim. Acta 2006, 359, 4235−4242. (56) Goodfellow, B. J.; Rusnak, F.; Moura, I.; Domke, T.; Moura, J. J. NMR determination of the global structure of the 113Cd derivative of desulforedoxin: Investigation of the hydrogen bonding pattern at the metal center. Protein Sci. 1998, 7, 928−937. (57) Baba, K.; Okamura, T.; Yamamoto, H.; Yamamoto, T.; Ueyama, N. Zinc, cadmium, and mercury 1, 2-benzenedithiolates with intramolecular NH···S hydrogen bonds. Inorg. Chem. 2008, 47, 2837−2848. (58) Chiou, S.-J.; Riordan, C. G.; Rheingold, A. L. Synthetic modeling of zinc thiolates: Quantitative assessment of hydrogen bonding in modulating sulfur alkylation rates. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 3695−3700. (59) Méplan, C.; Mann, K.; Hainaut, P. Cadmium induces conformational modifications of wild-type p53 and suppresses p53 response to DNA damage in cultured cells. J. Biol. Chem. 1999, 274, 31663−70. (60) Hanzawa, H.; de Ruwe, M. J.; Albert, T. K.; van Der Vliet, P. C.; Timmers, H. T.; Boelens, R. The structure of the C4C4 ring finger of human NOT4 reveals features distinct from those of C3HC4 RING fingers. J. Biol. Chem. 2001, 276, 10185−10190. (61) Kopera, E.; Schwerdtle, T.; Hartwig, A.; Bal, W. Co(II) and Cd(II) substitute for Zn(II) in the zinc finger derived from the DNA repair protein XPA, demonstrating a variety of potential mechanisms of toxicity. Chem. Res. Toxicol. 2004, 17, 1452−1458. (62) Kellenberger, E.; Dominguez, C.; Fribourg, S.; Wasielewski, E.; Moras, D.; Poterszman, A.; Boelens, R.; Kieffer, B. Solution structure of the C-terminal domain of TFIIH P44 subunit reveals a novel type of C4C4 ring domain involved in protein-protein interactions. J. Biol. Chem. 2005, 280, 20785−20792. (63) Mazmanian, K.; Sargsyan, K.; Grauffel, C.; Dudev, T.; Lim, C. Preferred Hydrogen-Bonding Partners of Cysteine: Implications for Regulating Cys Functions. J. Phys. Chem. B 2016, 120, 10288−10296. (64) Dennington, R.; Keith, T.; Millam, J. GaussView, Version 5; Semichem Inc.: Shawnee Mission, KS, 2009. (65) Grauffel, C.; Chu, B.; Lim, C. Factors Governing When a MetalBound Water is Deprotonated in Proteins. Chem. Sci. 2018, to be submitted. (66) Andrae, D.; Haeussermann, U.; Dolg, M.; Stoll, H.; Preuss, H. Energy-adjusted ab initio pseudopotentials for the second and third row transition elements. Theoret. Chim. Acta 1990, 77, 123−141. (67) Dolg, M.; Wedig, U.; Stoll, H.; Preuss, H. Energy-adjusted ab initio pseudopotentials for the first row transition elements. J. Chem. Phys. 1987, 86, 866−872. (68) McLean, A. D.; Chandler, G. S. Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z = 11−18. J. Chem. Phys. 1980, 72, 5639−5648. (69) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. Selfconsistent molecular orbital methods. XX. A basis set for correlated wave functions. J. Chem. Phys. 1980, 72, 650−654. (70) Wachters, A. J. H. Gaussian Basis Set for Molecular Wavefunctions Containing Third-Row Atoms. J. Chem. Phys. 1970, 52, 1033−1036. (71) Hay, P. J. Gaussian basis sets for molecular calculations. The representation of 3d orbitals in transition-metal atoms. J. Chem. Phys. 1977, 66, 4377−4384. (72) Del Bene, J. E. Basis set and correlation effects on computed hydrogen bond energies of the dimers (AHn)2: AHn = NH3, OH2, and FH. J. Chem. Phys. 1987, 86, 2110−2113. (73) Lynch, B. J.; Zhao, Y.; Truhlar, D. G. Effectiveness of Diffuse Basis Functions for Calculating Relative Energies by Density Functional Theory. J. Phys. Chem. A 2003, 107, 1384−1388. (74) Papajak, E.; Truhlar, D. G. Efficient Diffuse Basis Sets for Density Functional Theory. J. Chem. Theory Comput. 2010, 6, 597− 601.

(75) Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. The Cambridge Structural Database. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2016, 72, 171−179. (76) Frisch, M. J., Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 09, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2016. (77) Alecu, I. M.; Zheng, J.; Zhao, Y.; Truhlar, D. G. Computational Thermochemistry: Scale Factor Databases and Scale Factors for Vibrational Frequencies Obtained from Electronic Model Chemistries. J. Chem. Theory Comput. 2010, 6, 2872−2887. (78) Boese, A. D.; Handy, N. C. New exchange-correlation density functionals: The role of the kinetic-energy density. J. Chem. Phys. 2002, 116, 9559−9569. (79) Zhao, Y.; Pu, J.; Lynch, B. J.; Truhlar, D. G. Tests of secondgeneration and third-generation density functionals for thermochemical kinetics. Phys. Chem. Chem. Phys. 2004, 6, 673−676. (80) Gilson, M. K.; Sharp, K. A.; Honig, B. H. Calculating the electrostatic potential of molecules in solution: Method and error assessment. J. Comput. Chem. 1988, 9, 327−335. (81) Lim, C.; Bashford, D.; Karplus, M. Absolute Pka Calculations with Continuum Dielectric Methods. J. Phys. Chem. 1991, 95, 5610− 5620. (82) Bashford, D. An object-oriented programming suite for electrostatic effects in biological molecules. An experience report on the MEAD project. In Scientific Computing in Object-Oriented Parallel Environments; Ishikawa, Y., Oldehoeft, R., Reynders, J. W., Tholburn, M., Eds.; Springer: Berlin/Heidelberg, 1997; Vol. 1343, Chapter 30, pp 233−240. (83) Dudev, M.; Wang, J.; Dudev, T.; Lim, C. Factors governing the metal coordination number in metal complexes from Cambridge Structure Database analyses. J. Phys. Chem. B 2006, 110, 1889−1895. (84) Alongi, K. S.; Shields, G. C. Theoretical Calculations of Acid Dissociation Constants: A Review Article. In Annual Reports in Computational Chemistry; Wheeler, R. A., Ed.; Elsevier: Amsterdam, 2010; Vol. 6, Chapter 8, pp 113−138. (85) Kelly, C. P.; Cramer, C. J.; Truhlar, D. G. SM6: A Density Functional Theory Continuum Solvation Model for Calculating Aqueous Solvation Free Energies of Neutrals, Ions, and Solute− Water Clusters. J. Chem. Theory Comput. 2005, 1, 1133−1152. (86) Vorobyov, I.; Li, L.; Allen, T. W. Assessing atomistic and coarsegrained force fields for protein-lipid interactions: the formidable challenge of an ionizable side chain in a membrane. J. Phys. Chem. B 2008, 112, 9588−9602. (87) Wolfenden, R. Interaction of a peptide bond with solvent watervapor phase analysis. Biochemistry 1978, 17, 201−204. (88) Wolfenden, R.; Andersson, L.; Cullis, P. M.; Southgate, C. C. B. Affinities of Amino Acid Side Chains for Solvent Water. Biochemistry 1981, 20, 849−855. (89) Sitkoff, D.; Sharp, K. A.; Honig, B. Accurate calculation of hydration free energies using macroscopic solvent models. J. Phys. Chem. 1994, 98, 1978−1988. (90) Deepa, P.; Kolandaivel, P.; Senthilkumar, K. Hydrogen-bonding studies of amino acid side-chains with DNA base pairs. Mol. Phys. 2011, 109, 1995−2008. (91) Vallet, V.; Masella, M. Benchmark binding energies of ammonium and alkyl-ammonium ions interacting with water. Are I

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry ammonium−water hydrogen bonds strong? Chem. Phys. Lett. 2015, 618, 168−173. (92) Tang, S.; Zhao, H.; Du, L. Hydrogen bonding in alcohol− ethylene oxide and alcohol−ethylene sulfide complexes. RSC Adv. 2016, 6, 91233−91242. (93) Su, P.; Li, H. Energy decomposition analysis of covalent bonds and intermolecular interactions. J. Chem. Phys. 2009, 131, 014102. (94) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. General Atomic and Molecular Electronic Structure System. J. Comput. Chem. 1993, 14, 1347−1363. (95) Schuchardt, K. L.; Didier, B. T.; Elsethagen, T.; Sun, L.; Gurumoorthi, V.; Chase, J.; Li, J.; Windus, T. L. Basis Set Exchange: A Community Database for Computational Sciences. J. Chem. Inf. Model. 2007, 47, 1045−1052. (96) Linstrom, P.; Mallard, W. NIST Chemistry WebBook, NIST Standard Reference Database Number 69; National Institute of Standards and Technology: Gaithersburg, MD, 2003. (97) Hunter, E. P. L.; Lias, S. G. Evaluated Gas Phase Basicities and Proton Affinities of Molecules: An Update. J. Phys. Chem. Ref. Data 1998, 27, 413−656. (98) Gianola, A. J.; Ichino, T.; Hoenigman, R. L.; Kato, S.; Bierbaum, V. M.; Lineberger, W. C. J. Photoelectron Spectra and Ion Chemistry of Imidazolide. J. Phys. Chem. A 2005, 109, 11504−11514. (99) Ervin, K. M.; Nickel, A. A.; Lanorio, J. G.; Ghale, S. B. Anchoring the Gas-Phase Acidity Scale from Hydrogen Sulfide to Pyrrole. Experimental Bond Dissociation Energies of Nitromethane, Ethanethiol, and Cyclopentadiene. J. Phys. Chem. A 2015, 119, 7169− 7179. (100) Johnson, R. D., III. NIST Computational Chemistry Comparison and Benchmark Database, NIST Standard Reference Database Number 101, Release 18; http://cccbdb.nist.gov/. (101) Kang, C.; Korter, T. M.; Pratt, D. W. Experimental measurement of the induced dipole moment of an isolated molecule in its ground and electronically excited states: Indole and indole− H2O. J. Chem. Phys. 2005, 122, 174301. (102) Cheam, T. C.; Krimm, S. Infrared intensities of amide modes in N-methylacetamide and poly(glycine I) from ab initio calculations of dipole moment derivatives of N-methylacetamide. J. Chem. Phys. 1985, 82, 1631−1641. (103) Christen, D.; Griffiths, J.; Sheridan, J. The Microwave Spectrum of Imidazole; Complete Structure and the Electron Distribution from Nuclear Quadrupole Coupling Tensors and Dipole Moment Orientation. Z. Naturforsch., A: Phys. Sci. 1982, 37a, 1378− 1385. (104) Daley, R. F.; Daley, S. J. Organic Chemistry, Part 1 of 3; Daley Press, 2013; p 395. (105) Walba, H.; Isensee, R. W. Acidity Constants of Some Arylimidazoles and Their Cations. J. Org. Chem. 1961, 26, 2789−2791. (106) Rynkiewicz, M. J.; Seaton, B. A. Chemical Rescue by Guanidine Derivatives of an Arginine-Substituted Site-Directed Mutant of Escherichia coli Ornithine Transcarbamylase. Biochemistry 1996, 35, 16174−16179. (107) Shannon, R. D. Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides. Acta Crystallogr., Sect. A: Cryst. Phys., Diffr., Theor. Gen. Crystallogr. 1976, 32, 751−767. (108) Kuppuraj, G.; Dudev, M.; Lim, C. Factors governing metal− ligand distances and coordination geometries of metal complexes. J. Phys. Chem. B 2009, 113, 2952−2960. (109) Borovik, A. S. Bioinspired hydrogen bond motifs in ligand design: the role of noncovalent interactions in metal ion mediated activation of dioxygen. Acc. Chem. Res. 2005, 38, 54−61. (110) Lin, Y.-W. Rational design of metalloenzymes: From single to multiple active sites. Coordination Chemistry Reviews. Coord. Chem. Rev. 2017, 336, 1−27. (111) Zastrow, M. L.; Pecoraro, V. L. Designing hydrolytic zinc metalloenzymes. Biochemistry 2014, 53, 957−978.

(112) Tekeste, T.; Vahrenkamp, H. Modeling zinc enzyme inhibition with functional thiolate ligands. Inorg. Chem. 2006, 45, 10799−10806. (113) Jiang, P.; Guo, Z. Fluorescent detection of zinc in biological systems: recent development on the design of chemosensors and biosensors. Coord. Chem. Rev. 2004, 248, 205−229. (114) Foster, M. P.; Wuttke, D. S.; Radhakrishnan, I.; Case, D. A.; Gottesfeld, J. M.; Wright, P. E. Domain packing and dynamics in the DNA complex of the N-terminal zinc fingers of TFIIIA. Nat. Struct. Biol. 1997, 4, 605−608. (115) Hanas, J. S.; Gunn, C. G. Inhibition of transcription factor IIIADNA interactions by xenobiotic metal ions. Nucleic Acids Res. 1996, 24, 924−930. (116) Dołęga, A.; Baranowska, K.; Gajda, J.; Kaźmierski, S.; Potrzebowski, M. J. Cadmium tri-tert-butoxysilanethiolates: Structural and spectroscopic models of metal sites in proteins. Inorg. Chim. Acta 2007, 360, 2973−2982. (117) Chakraborty, S.; Iranzo, O.; Zuiderweg, E. R. P.; Pecoraro, V. L. Experimental and Theoretical Evaluation of Multisite Cadmium(II) Exchange in Designed Three-Stranded Coiled-Coil Peptides. J. Am. Chem. Soc. 2012, 134, 6191−6203.

J

DOI: 10.1021/acs.inorgchem.8b01029 Inorg. Chem. XXXX, XXX, XXX−XXX