This article was downloaded by: [Florida State University] On: 22 December 2014, At: 05:26 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Biomolecular Structure and Dynamics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tbsd20
Electronic structure of alloxan and its dimers: QM/QD simulations and quantum chemical topology analysis a
ab
a
ac
Basmah H. Allehyani , Shaaban A. Elroby , Saadalluh.G. Aziz & Rifaat H. Hilal a
Chemistry Department, Faculty of Science, King Abdul-Aziz University, Jeddah, Saudi Arabia b
Chemistry Department, Faculty of Science, Beni Suef University, Beni Suef, Egypt
c
Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt Accepted author version posted online: 11 Dec 2014.
Click for updates To cite this article: Basmah H. Allehyani, Shaaban A. Elroby, Saadalluh.G. Aziz & Rifaat H. Hilal (2014): Electronic structure of alloxan and its dimers: QM/QD simulations and quantum chemical topology analysis, Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2014.997291 To link to this article: http://dx.doi.org/10.1080/07391102.2014.997291
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Publisher: Taylor & Francis Journal: Journal of Biomolecular Structure and Dynamics DOI: http://dx.doi.org/10.1080/07391102.2014.997291
Downloaded by [Florida State University] at 05:27 22 December 2014
Electronic structure of alloxan and its dimers: QM/QD simulations and quantum chemical topology analysis Basmah H.Allehyani 1, Shaaban A. Elroby1,2, Saadalluh.G. Aziz1, Rifaat H. Hilal1,3*
1
Chemistry Department, Faculty of Science, King Abdul-Aziz University, Jeddah, Saudi Arabia
2
Chemistry Department, Faculty of Science, Beni Suef University, Beni Suef, Egypt
3
Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt
Abstract: This study aims to identify the origin of the extra stability of alloxan, a biologically active pyrimidine. To achieve this goal, detailed DFT computations and quantum dynamics simulations have been performed to establish the most stable conformation and the global minimum structure on the alloxan potential energy surface. The effects of the solvent, basis set and DFT method have been examined to validate the theoretical model adopted throughout the work. Two non-covalent intermolecular dimers of alloxan, the H-bonded and dipolar dimers, have been investigated at the ωB97X-D and M06-2X levels of theory using the triple zeta 6-311++G** to establish their relative stability. Quantum chemical topology features and natural bond orbital analysis (NBO) have been performed to identify and characterize the forces that govern the structures and underlie the extra stability of alloxan.
Key words: Alloxan, DFT, quantum dynamic simulation, quantum chemical topology, Extra stability, QTAIM.
*To whom all correspondence should be addressed: [email protected] 1
Downloaded by [Florida State University] at 05:27 22 December 2014
1. Introduction Alloxan,(2,4,5,6-tetraoxypyrimidine ;2,4,5,6- pyrimidine tetrone) is an oxygenated pyrimidine derivative; a toxic glucose analogue, which selectively destroys insulin-producing cells in the pancreas (that is beta cells) when administered to rodents and many other animal species[1,2]. Alloxan is a poor nucleophile compared to pyrimidine, but is a very strong electrophile and is antiaromatic. Alloxan (I) has been widely regarded as a ‘‘problem structure" because it contains four C=O proton acceptor groups and two N-H proton donor groups, yet its x-ray structure suggests the absence of ‘‘conventional’’ hydrogen bonds. Indeed, the structure showed intermolecular (N)H---O distances that are less than the sum of the corresponding van der Waals radii but they were longer than the typical (N)H---O hydrogen bond distance of about 1.7 Å [3]. Nevertheless, alloxan is characterized by a remarkable stability and unusually high melting point. Furthermore, although all experimental[4-6] and theoretical studies[7-10] concluded that the tetra keto form of alloxan is the most stable, nevertheless, this would not explain the relative strong acidity of alloxan as manifested by a pKa value of 6.63 [11]. The present work aims to explore the origin of the extra stability of alloxan. Thus, all possible tautomeric and rotomeric forms of alloxan will be considered to establish the most stable form in both the gas phase and in solution. Non-covalent intermolecular interactions involving alloxan will be investigated to establish their relative stability. Quantum dynamics simulations are then conducted starting from the optimized geometric structure to explore regions around and in the immediate vicinity on the PES to establish their global minimum structures. Quantum chemical topology features and natural bond orbital analysis are performed to identify and characterize the forces that govern the structures of the studied clusters.
2. Computational methods
2
All calculations have been carried out using the Gaussian 09 package [12] of programs. The geometries of alloxan and its tautomers, have been fully optimized at the DFT/B3LYP using several different basis sets, namely the 6-311++G**, the aug-cc-pVXZ ( X=2, and 3) basis sets [13-15]. Frequency calculations were performed at the same level of theory in order to characterize stationary points and to evaluate the zero-point energy. The stable alloxan conformer was subjected to further confirmation and validation using other functionals, namely ωB97X-D [16] and M06-2X [17,18] methods, using the same basis set. M06-2X is claimed to capture ’’medium-range’’ electron correlation; however, the ’’long-range’’ electron correlation
Downloaded by [Florida State University] at 05:27 22 December 2014
neglected by this functional can also be important in the binding of noncovalent complex. All clusters studied were also fully optimized at the ωB97X-D and M06-2X levels of theory using the triple zeta 6-311++G** basis set. The DFT-D approach of Grimme is used to explore the weak interactions in dimers of alloxan. The DFT-D method is a widely applicable method for correcting the performance of standard density functionals. This method utilizes a damped R-6 term to model the dispersion interactions (eqs 1, 2, and 3).
Basis set superposition error (BSSE) have been estimated using the counterpoise (CP) method of Boys and Bernardi [19]. The Boys and Bernardi counterpoise correction (CP) is a prescription for removing BSSE. The typical, uncorrected interaction energy between monomers A and B would be computed as: ∆Eint(AB) =EABσAB (AB)−EAσA(A)−EBσB(B) where the superscripts denote the basis used, the subscripts denote the geometry, and the symbol in parentheses denotes the chemical system considered. Thus, EABσAB (AB) represents the energy of the bimolecular complex AB evaluated in the dimer basis (the union of the basis sets on A and B), computed at the geometry of the dimer. Solvent effects have been considered using solvent continuum model, namely the PCM model. Quantum chemical topology analysis was carried out at the quantum theory of atoms in molecules[20] (QTAIM) level of theory through the program AIMAll [21-24]. Hyper conjugative [25] interactions have been computed and analyzed using the Natural Bond Orbital 3
(NBO) theory. Throughout this work molecular orbitals and electrostatic potential maps were constructed using Gauss View 5.0.8 visualization program [26]. Classical trajectory dynamic simulations [27,28] have been performed using the Atom Centered Density Matrix Propagation(ADMP) molecular dynamics model [29-31]. ADMP belongs to the extended Lagrangian approach to molecular dynamics using Gaussian basis functions and propagating the density matrix. The best known method of this type is Car-Parrinello (CP) molecular dynamics [30], in which the Kohn-Sham molecular orbitals, ψi, are chosen as the dynamical variables to represent the electronic degrees of freedom in the system. CP calculations are usually carried out in a plane wave basis (although Gaussian orbitals are sometimes added as Downloaded by [Florida State University] at 05:27 22 December 2014
an adjunct [31]). Unlike plane wave CP, it is not necessary to use pseudopotentials on hydrogen or to use deuterium rather than hydrogen in the dynamics. Fictitious masses for the electronic degrees of freedom are set automatically [29] and can be small enough that thermostats are not required for good energy conservation. In the trajectory simulation the temperature is kept constant at 300 K.
4
Downloaded by [Florida State University] at 05:27 22 December 2014
3. Results and discussion:
3. 1. Tautomeric Forms
5
Fig. 1. Tautomers and rotamers of alloxan adopted in the present work.
All possible tautomeric , rotameric and one zwitterion forms of alloxan are displayed in figure 1 and the corresponding relative energies are presented in table 1. The tetra keto form is the most stable form. In gas phase, the relative stability of alloxan tautomers and rotamers is in the order, 4-hydroxy < 2-hydroxy < 2,4-dihydroxy < 4,6-dihydroxy ( IIIA < IIB < IIA
Journal of Biomolecular Structure and Dynamics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tbsd20
Electronic structure of alloxan and its dimers: QM/QD simulations and quantum chemical topology analysis a
ab
a
ac
Basmah H. Allehyani , Shaaban A. Elroby , Saadalluh.G. Aziz & Rifaat H. Hilal a
Chemistry Department, Faculty of Science, King Abdul-Aziz University, Jeddah, Saudi Arabia b
Chemistry Department, Faculty of Science, Beni Suef University, Beni Suef, Egypt
c
Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt Accepted author version posted online: 11 Dec 2014.
Click for updates To cite this article: Basmah H. Allehyani, Shaaban A. Elroby, Saadalluh.G. Aziz & Rifaat H. Hilal (2014): Electronic structure of alloxan and its dimers: QM/QD simulations and quantum chemical topology analysis, Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2014.997291 To link to this article: http://dx.doi.org/10.1080/07391102.2014.997291
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Publisher: Taylor & Francis Journal: Journal of Biomolecular Structure and Dynamics DOI: http://dx.doi.org/10.1080/07391102.2014.997291
Downloaded by [Florida State University] at 05:27 22 December 2014
Electronic structure of alloxan and its dimers: QM/QD simulations and quantum chemical topology analysis Basmah H.Allehyani 1, Shaaban A. Elroby1,2, Saadalluh.G. Aziz1, Rifaat H. Hilal1,3*
1
Chemistry Department, Faculty of Science, King Abdul-Aziz University, Jeddah, Saudi Arabia
2
Chemistry Department, Faculty of Science, Beni Suef University, Beni Suef, Egypt
3
Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt
Abstract: This study aims to identify the origin of the extra stability of alloxan, a biologically active pyrimidine. To achieve this goal, detailed DFT computations and quantum dynamics simulations have been performed to establish the most stable conformation and the global minimum structure on the alloxan potential energy surface. The effects of the solvent, basis set and DFT method have been examined to validate the theoretical model adopted throughout the work. Two non-covalent intermolecular dimers of alloxan, the H-bonded and dipolar dimers, have been investigated at the ωB97X-D and M06-2X levels of theory using the triple zeta 6-311++G** to establish their relative stability. Quantum chemical topology features and natural bond orbital analysis (NBO) have been performed to identify and characterize the forces that govern the structures and underlie the extra stability of alloxan.
Key words: Alloxan, DFT, quantum dynamic simulation, quantum chemical topology, Extra stability, QTAIM.
*To whom all correspondence should be addressed: [email protected] 1
Downloaded by [Florida State University] at 05:27 22 December 2014
1. Introduction Alloxan,(2,4,5,6-tetraoxypyrimidine ;2,4,5,6- pyrimidine tetrone) is an oxygenated pyrimidine derivative; a toxic glucose analogue, which selectively destroys insulin-producing cells in the pancreas (that is beta cells) when administered to rodents and many other animal species[1,2]. Alloxan is a poor nucleophile compared to pyrimidine, but is a very strong electrophile and is antiaromatic. Alloxan (I) has been widely regarded as a ‘‘problem structure" because it contains four C=O proton acceptor groups and two N-H proton donor groups, yet its x-ray structure suggests the absence of ‘‘conventional’’ hydrogen bonds. Indeed, the structure showed intermolecular (N)H---O distances that are less than the sum of the corresponding van der Waals radii but they were longer than the typical (N)H---O hydrogen bond distance of about 1.7 Å [3]. Nevertheless, alloxan is characterized by a remarkable stability and unusually high melting point. Furthermore, although all experimental[4-6] and theoretical studies[7-10] concluded that the tetra keto form of alloxan is the most stable, nevertheless, this would not explain the relative strong acidity of alloxan as manifested by a pKa value of 6.63 [11]. The present work aims to explore the origin of the extra stability of alloxan. Thus, all possible tautomeric and rotomeric forms of alloxan will be considered to establish the most stable form in both the gas phase and in solution. Non-covalent intermolecular interactions involving alloxan will be investigated to establish their relative stability. Quantum dynamics simulations are then conducted starting from the optimized geometric structure to explore regions around and in the immediate vicinity on the PES to establish their global minimum structures. Quantum chemical topology features and natural bond orbital analysis are performed to identify and characterize the forces that govern the structures of the studied clusters.
2. Computational methods
2
All calculations have been carried out using the Gaussian 09 package [12] of programs. The geometries of alloxan and its tautomers, have been fully optimized at the DFT/B3LYP using several different basis sets, namely the 6-311++G**, the aug-cc-pVXZ ( X=2, and 3) basis sets [13-15]. Frequency calculations were performed at the same level of theory in order to characterize stationary points and to evaluate the zero-point energy. The stable alloxan conformer was subjected to further confirmation and validation using other functionals, namely ωB97X-D [16] and M06-2X [17,18] methods, using the same basis set. M06-2X is claimed to capture ’’medium-range’’ electron correlation; however, the ’’long-range’’ electron correlation
Downloaded by [Florida State University] at 05:27 22 December 2014
neglected by this functional can also be important in the binding of noncovalent complex. All clusters studied were also fully optimized at the ωB97X-D and M06-2X levels of theory using the triple zeta 6-311++G** basis set. The DFT-D approach of Grimme is used to explore the weak interactions in dimers of alloxan. The DFT-D method is a widely applicable method for correcting the performance of standard density functionals. This method utilizes a damped R-6 term to model the dispersion interactions (eqs 1, 2, and 3).
Basis set superposition error (BSSE) have been estimated using the counterpoise (CP) method of Boys and Bernardi [19]. The Boys and Bernardi counterpoise correction (CP) is a prescription for removing BSSE. The typical, uncorrected interaction energy between monomers A and B would be computed as: ∆Eint(AB) =EABσAB (AB)−EAσA(A)−EBσB(B) where the superscripts denote the basis used, the subscripts denote the geometry, and the symbol in parentheses denotes the chemical system considered. Thus, EABσAB (AB) represents the energy of the bimolecular complex AB evaluated in the dimer basis (the union of the basis sets on A and B), computed at the geometry of the dimer. Solvent effects have been considered using solvent continuum model, namely the PCM model. Quantum chemical topology analysis was carried out at the quantum theory of atoms in molecules[20] (QTAIM) level of theory through the program AIMAll [21-24]. Hyper conjugative [25] interactions have been computed and analyzed using the Natural Bond Orbital 3
(NBO) theory. Throughout this work molecular orbitals and electrostatic potential maps were constructed using Gauss View 5.0.8 visualization program [26]. Classical trajectory dynamic simulations [27,28] have been performed using the Atom Centered Density Matrix Propagation(ADMP) molecular dynamics model [29-31]. ADMP belongs to the extended Lagrangian approach to molecular dynamics using Gaussian basis functions and propagating the density matrix. The best known method of this type is Car-Parrinello (CP) molecular dynamics [30], in which the Kohn-Sham molecular orbitals, ψi, are chosen as the dynamical variables to represent the electronic degrees of freedom in the system. CP calculations are usually carried out in a plane wave basis (although Gaussian orbitals are sometimes added as Downloaded by [Florida State University] at 05:27 22 December 2014
an adjunct [31]). Unlike plane wave CP, it is not necessary to use pseudopotentials on hydrogen or to use deuterium rather than hydrogen in the dynamics. Fictitious masses for the electronic degrees of freedom are set automatically [29] and can be small enough that thermostats are not required for good energy conservation. In the trajectory simulation the temperature is kept constant at 300 K.
4
Downloaded by [Florida State University] at 05:27 22 December 2014
3. Results and discussion:
3. 1. Tautomeric Forms
5
Fig. 1. Tautomers and rotamers of alloxan adopted in the present work.
All possible tautomeric , rotameric and one zwitterion forms of alloxan are displayed in figure 1 and the corresponding relative energies are presented in table 1. The tetra keto form is the most stable form. In gas phase, the relative stability of alloxan tautomers and rotamers is in the order, 4-hydroxy < 2-hydroxy < 2,4-dihydroxy < 4,6-dihydroxy ( IIIA < IIB < IIA
