The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme.... more The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functional activities. Here, we address the redox-dependent conformational dynamics of hPDI through molecular dynamics (MD) simulations. Collective domain motions are identified by the principal component analysis of MD trajectories and redox-dependent opening-closing structure variations are highlighted on projected free energy landscapes. Then, important structural features that exhibit considerable differences in dynamics of redox states are extracted by statistical machine learning methods. Mapping the structural variations to time series of residue interaction networks also provides a holistic representation of the dynamical redox differences. With emphasizing on persistent long-lasting interactions, ...
Human protein disulfide isomerase (hPDI) is a key redox-regulated thiol-containing protein operat... more Human protein disulfide isomerase (hPDI) is a key redox-regulated thiol-containing protein operating as both oxidoreductase and molecular chaperone in the endoplasmic reticulum of cells. hPDI thiol-disulfide interchange reactions lead to the adoption of two distinct red/ox conformations with different substrate preferences. hPDI also displays high binding capacity for some endogenous steroid hormones including 17 beta-estradiol (E2) and thus contributes to the regulation of their intracellular concentration, storage and actions. The primary focus of this study was to investigate the impact of E2 binding on functional activity of recombinant hPDI. Then, we examined the effect of E2 binding on structural alteration of hPDI red/ox conformations and its influence on affinity and position of interaction using experimental and computational analysis. Our results revealed that interaction of one E2 per each hPDI molecule led to the inhibition of hPDI reductase activity and conformational c...
Ligand binding studies on human serum albumin (HSA) are crucial in determining the pharmacologica... more Ligand binding studies on human serum albumin (HSA) are crucial in determining the pharmacological properties of drug candidates. Here, two representatives of coumarin-chalcone hybrids were selected and their binding mechanism was identified via thermodynamics techniques, curve resolution analysis and computational methods at molecular levels. The binding parameters were derived using spectroscopic approaches and the results point to only one pocket located near the Trp214 residue in subdomain IIA of HSA. The protein tertiary structure was altered during ligand binding and formed an intermediate structure to create stronger ligand binding interactions. The best binding mode of the ligand was initially estimated by docking on an ensemble of HSA crystallographic structures and by molecular dynamics (MD) simulations. Per residue interaction energies were calculated over the MD trajectories as well. Reasonable agreement was found between experimental and theoretical results about the nature of binding, which was dominated by hydrogen bonding and van der Waals contributions.
The critical role of carbonic anhydrases in different physiological processes has put this protei... more The critical role of carbonic anhydrases in different physiological processes has put this protein family at the center of attention, challenging major diseases like glaucoma, neurological disorders such as epilepsy and Alzheimer's disease, obesity and cancers. Many QSAR/QSPR (quantitative structure activity/property relationship) researches have been done to design potent carbonic anhydrase inhibitors (CAIs); however using inhibitors with no selectivity for different isoforms can lead to major side effects. Given that QSAR/QSPR methods are not capable of covering multiple targets in a unified model, we have applied the proteochemometrics approach to model the interaction space that governs selective inhibition of different CA isoforms by some mono-/dihydroxybenzoic acid esters. Internal and external validation methods showed that all models were reliable in terms of both validity and predictivity, whereas Y-scrambling assessed the robustness of the models. To prove the applicab...
Bisphosphonates are important therapeutic agents in bone-related diseases and exhibit complex H-b... more Bisphosphonates are important therapeutic agents in bone-related diseases and exhibit complex H-bonding networks. To assess the role of H-bonds in biophosphonate stability, a full conformational search was performed for methylenebisphosphonate (MBP) and 1-hydroxyethylidene-1,1-diphosphonate (HEDP) using the MP2 method in conjunction with the continuum solvation model. The most stable structures and their equilibrium populations were analyzed at two protonation states via assignment of H-bonding motifs to each conformer. Geometrical and topological approaches for the identification and characterization of H-bonds were compared with each other, and some of the important correlations between H-bond features were described over the entire conformational space of a hydroxy-bisphosphonate moiety. The topologically derived H-bond energy obtained from the local density of potential energy at bond critical points shows consistent correlations with other measures such as H-bond frequency shift. An inverse power form without an intercept predicts topological H-bond energies from hydrogen-acceptor distances with an RMS error of less than 1 kcal mol(-1). The consistency of this measure was further checked by building a model that reasonably reproduces the relative stabilities of different conformers from their hydrogen-acceptor distances. In all systems, the predictions of this model are improved by the consideration of weak H-bonds that have no bond critical point.
ABSTRACT We reported a quantum mechanical study of the complexes formed between Sm3+ and the bisp... more ABSTRACT We reported a quantum mechanical study of the complexes formed between Sm3+ and the bisphosphonate ligand pamidronate in aqueous solution. According to available experimental pKa values pamidronate was expected to exist in aqueous solution, at physiologically relevant pH, in its di- and tri-protonated forms (denoted by H3L and H2L). The most stable structures of the ligands and Sm3+ complexes were found by using a detailed analysis of the conformational space with semiempirical and DFT methods. The results showed that both H2L and H3L bisphosphonates acted as a tridentate ligands in their complexes with Sm3+. The addition of explicit water molecules to the coordination sphere of the metal not only gave different coordination numbers for H2L and H3L complexes (CN=9 and 10), but also provided different trends in stabilization energies. The results highlighted the importance of considering not only an explicit first coordination shell, but also a second hydration shell, for an adequate description of this type of complexes in aqueous solution.
2009 International Conference on Signal Processing Systems, 2009
AbstractA new interaction potential energy surface for the F2 dimer has recently derived from th... more AbstractA new interaction potential energy surface for the F2 dimer has recently derived from the quantum-mechanical ab initio calculations and described with a suitable analytical representation. In this work, our previous results of interaction potential energy surface for ...
Extensive DFT and ab initio calculations were performed
to characterize the conformational space ... more Extensive DFT and ab initio calculations were performed to characterize the conformational space of pamidronate, a typical pharmaceutical for bone diseases. Mono-, diand tri-protic states of molecule, relevant for physiological pH range, were investigated for both canonical and zwitterionic tautomers. Semiempirical PM6 method were used for prescreening of the single bond rotamers followed by geometry optimizations at the B3LYP/6-31++G(d,p) and B3LYP/6- 311++G(d,p) levels. For numerous identified low energy conformers the final electronic energies were determined at the MP2/6-311++G(2df,2p) level and corrected for thermal effects at B3LYP level. Solvation effects were also considered via the COSMO and C-PCM implicit models. Reasonable agreement was found between bond lengths and angle values in comparison with X-ray crystal structures. Relative equilibrium populations of different conformers were determined from molecular partition functions and the role of electronic, vibrational and rotational degrees of freedom on the stability of conformers were analyzed. For no level of theory is a zwitterionic structure stable in the gas-phase while solvation makes them available depending on the protonation state. Geometrically identified intramolecular hydrogen bonds were analyzed by QTAIM approach. All conformers exhibit strong inter-phosphonate hydrogen bonds and in most of them the alkyl-amine side chain is folded on the P-C-P backbone for further hydrogen bond formation.
Based on definition of angular central moments, a quantitative measure is proposed for comparativ... more Based on definition of angular central moments, a quantitative measure is proposed for comparative assessment of the anisotropy of different intermolecular potential energy surfaces at different intermolecular distances. Angular spreadness, skewness and peakedness are three features of anisotropy that are used here to describe the distribution of values of interaction energy around its isotropic component. In agreement with qualitative interpretations, the proposed measure exhibits a sharp change in the R-dependent pattern of anisotropy at an intermediate distance where the repulsive forces on the average overcome the attractive ones. The R-dependence of anisotropy of available N2–N2 potentials is examined in comparison with bare ab initio data and considerable discrepancies are found at distances shorter than the onset of repulsion. It is shown that the full experimentally derived potentials with simplified functional forms do not reproduce the correct anisotropy of interaction energy.
In this work, for the first time, an analytical four-dimensional representation for the intermole... more In this work, for the first time, an analytical four-dimensional representation for the intermolecular potential of the N(2)-CO dimer is constructed from ab initio calculations. The most stable structure of dimer is found to be a distorted T-shape conformation with CO forming the top and N(2) the leg of T. Important structures of the dimer are characterized, and surprisingly, it is found that in contrast with general assumptions, the potential energy surface of the N(2)-CO dimer has a single symmetry unique minimum. The energy profile of a minimum energy path that connects two T-shaped saddle points to the minimum structure is derived. Important structures are characterized along this path to represent the concerted internal rotation of monomers within the complex. The second virial coefficient is calculated from the fitted PES, and reasonable agreement is found with recent experimental results.
The intermolecular potential energy surface (PES) of the Cl2 dimer is calculated at the MP2/aTZ +... more The intermolecular potential energy surface (PES) of the Cl2 dimer is calculated at the MP2/aTZ + b level of ab initio theory. A quantitative measure is proposed for comparison of the anisotropy of PESs of different systems at different intermolecular distances. A high degree of anisotropy at short and intermediate distances results in the failure of fitting strategies that are based on the angular expansion of the potential energy. To tackle this problem, a step-by-step fitting strategy is designed for analytical representation of the PES. The global minimum energy configuration of the dimer is found to be a distorted L-shape structure with a well depth of around 615 cm−1. The PES is finally scaled to minimize deviations between calculated and experimental second virial coefficients.
Two analytical representations for the potential energy surface of the F2 dimer were constructed ... more Two analytical representations for the potential energy surface of the F2 dimer were constructed on the basis of ab initio calculations up to the fourth-order of Møller−Plesset (MP) perturbation theory. The best estimate of the complete basis set limit of interaction energy was derived for analysis of basis set incompleteness errors. At the MP4/aug-cc-pVTZ level of theory, the most stable structure of the dimer was obtained at R = 6.82 au, θa = 12.9°, θb = 76.0°, and φ = 180°, with a well depth of 716 μEh. Two other minima were found for canted and X-shaped configurations with potential energies around −596 and −629 μEh, respectively. Hexadecapole moments of monomers play an important role in the anisotropy of interaction energy that is highly R-dependent at intermediate intermolecular distances. The quality of potentials was tested by computing values of the second virial coefficient. The fitted MP4 potential has a more reasonable agreement with experimental values.
A recent N2–N2 potential has been used to calculate the second virial, viscosity, and diffusion c... more A recent N2–N2 potential has been used to calculate the second virial, viscosity, and diffusion coefficients. Calculations have been done up to the first quantum correction for virial coefficients and the second-order kinetic theory approximation for transport coefficients. The Mason–Monchick approximation (MMA) has been used for the calculation of collision integrals and, via a numerical analysis, a common intersection point has been found for reduced cross sections and collision integrals of different orientations. This regularity has been interpreted with the aim of the orientation dependence of the potential energy and different types of collisions between molecules. The overall agreement of the calculated second virial coefficient with experiment is reasonable but suggests that a slight re-scaling of the potential would be beneficial. In the case of transport properties, calculated and experimental results show an average deviation of about 1.6% and 0.7% for viscosity and relative diffusion coefficients, respectively.
A new four-dimensional potential energy surface has been developed for N2 dimer. Ab initio calcul... more A new four-dimensional potential energy surface has been developed for N2 dimer. Ab initio calculations were performed with the cc-pVXZ correlation consistent basis set. For calculating the PES of the N2 dimer, we have chosen to follow the supermolecular Møller–Plesset perturbation theory up to second order (MP2). Our MP2 results show that the most stable structure of N2 dimer is the slipped parallel form with θa = 50, θb = 50, phi = 0 conformation with 7.7 a.u. and 487.6 μH values of equilibrium distance and energy.
The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme.... more The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functional activities. Here, we address the redox-dependent conformational dynamics of hPDI through molecular dynamics (MD) simulations. Collective domain motions are identified by the principal component analysis of MD trajectories and redox-dependent opening-closing structure variations are highlighted on projected free energy landscapes. Then, important structural features that exhibit considerable differences in dynamics of redox states are extracted by statistical machine learning methods. Mapping the structural variations to time series of residue interaction networks also provides a holistic representation of the dynamical redox differences. With emphasizing on persistent long-lasting interactions, ...
Human protein disulfide isomerase (hPDI) is a key redox-regulated thiol-containing protein operat... more Human protein disulfide isomerase (hPDI) is a key redox-regulated thiol-containing protein operating as both oxidoreductase and molecular chaperone in the endoplasmic reticulum of cells. hPDI thiol-disulfide interchange reactions lead to the adoption of two distinct red/ox conformations with different substrate preferences. hPDI also displays high binding capacity for some endogenous steroid hormones including 17 beta-estradiol (E2) and thus contributes to the regulation of their intracellular concentration, storage and actions. The primary focus of this study was to investigate the impact of E2 binding on functional activity of recombinant hPDI. Then, we examined the effect of E2 binding on structural alteration of hPDI red/ox conformations and its influence on affinity and position of interaction using experimental and computational analysis. Our results revealed that interaction of one E2 per each hPDI molecule led to the inhibition of hPDI reductase activity and conformational c...
Ligand binding studies on human serum albumin (HSA) are crucial in determining the pharmacologica... more Ligand binding studies on human serum albumin (HSA) are crucial in determining the pharmacological properties of drug candidates. Here, two representatives of coumarin-chalcone hybrids were selected and their binding mechanism was identified via thermodynamics techniques, curve resolution analysis and computational methods at molecular levels. The binding parameters were derived using spectroscopic approaches and the results point to only one pocket located near the Trp214 residue in subdomain IIA of HSA. The protein tertiary structure was altered during ligand binding and formed an intermediate structure to create stronger ligand binding interactions. The best binding mode of the ligand was initially estimated by docking on an ensemble of HSA crystallographic structures and by molecular dynamics (MD) simulations. Per residue interaction energies were calculated over the MD trajectories as well. Reasonable agreement was found between experimental and theoretical results about the nature of binding, which was dominated by hydrogen bonding and van der Waals contributions.
The critical role of carbonic anhydrases in different physiological processes has put this protei... more The critical role of carbonic anhydrases in different physiological processes has put this protein family at the center of attention, challenging major diseases like glaucoma, neurological disorders such as epilepsy and Alzheimer's disease, obesity and cancers. Many QSAR/QSPR (quantitative structure activity/property relationship) researches have been done to design potent carbonic anhydrase inhibitors (CAIs); however using inhibitors with no selectivity for different isoforms can lead to major side effects. Given that QSAR/QSPR methods are not capable of covering multiple targets in a unified model, we have applied the proteochemometrics approach to model the interaction space that governs selective inhibition of different CA isoforms by some mono-/dihydroxybenzoic acid esters. Internal and external validation methods showed that all models were reliable in terms of both validity and predictivity, whereas Y-scrambling assessed the robustness of the models. To prove the applicab...
Bisphosphonates are important therapeutic agents in bone-related diseases and exhibit complex H-b... more Bisphosphonates are important therapeutic agents in bone-related diseases and exhibit complex H-bonding networks. To assess the role of H-bonds in biophosphonate stability, a full conformational search was performed for methylenebisphosphonate (MBP) and 1-hydroxyethylidene-1,1-diphosphonate (HEDP) using the MP2 method in conjunction with the continuum solvation model. The most stable structures and their equilibrium populations were analyzed at two protonation states via assignment of H-bonding motifs to each conformer. Geometrical and topological approaches for the identification and characterization of H-bonds were compared with each other, and some of the important correlations between H-bond features were described over the entire conformational space of a hydroxy-bisphosphonate moiety. The topologically derived H-bond energy obtained from the local density of potential energy at bond critical points shows consistent correlations with other measures such as H-bond frequency shift. An inverse power form without an intercept predicts topological H-bond energies from hydrogen-acceptor distances with an RMS error of less than 1 kcal mol(-1). The consistency of this measure was further checked by building a model that reasonably reproduces the relative stabilities of different conformers from their hydrogen-acceptor distances. In all systems, the predictions of this model are improved by the consideration of weak H-bonds that have no bond critical point.
ABSTRACT We reported a quantum mechanical study of the complexes formed between Sm3+ and the bisp... more ABSTRACT We reported a quantum mechanical study of the complexes formed between Sm3+ and the bisphosphonate ligand pamidronate in aqueous solution. According to available experimental pKa values pamidronate was expected to exist in aqueous solution, at physiologically relevant pH, in its di- and tri-protonated forms (denoted by H3L and H2L). The most stable structures of the ligands and Sm3+ complexes were found by using a detailed analysis of the conformational space with semiempirical and DFT methods. The results showed that both H2L and H3L bisphosphonates acted as a tridentate ligands in their complexes with Sm3+. The addition of explicit water molecules to the coordination sphere of the metal not only gave different coordination numbers for H2L and H3L complexes (CN=9 and 10), but also provided different trends in stabilization energies. The results highlighted the importance of considering not only an explicit first coordination shell, but also a second hydration shell, for an adequate description of this type of complexes in aqueous solution.
2009 International Conference on Signal Processing Systems, 2009
AbstractA new interaction potential energy surface for the F2 dimer has recently derived from th... more AbstractA new interaction potential energy surface for the F2 dimer has recently derived from the quantum-mechanical ab initio calculations and described with a suitable analytical representation. In this work, our previous results of interaction potential energy surface for ...
Extensive DFT and ab initio calculations were performed
to characterize the conformational space ... more Extensive DFT and ab initio calculations were performed to characterize the conformational space of pamidronate, a typical pharmaceutical for bone diseases. Mono-, diand tri-protic states of molecule, relevant for physiological pH range, were investigated for both canonical and zwitterionic tautomers. Semiempirical PM6 method were used for prescreening of the single bond rotamers followed by geometry optimizations at the B3LYP/6-31++G(d,p) and B3LYP/6- 311++G(d,p) levels. For numerous identified low energy conformers the final electronic energies were determined at the MP2/6-311++G(2df,2p) level and corrected for thermal effects at B3LYP level. Solvation effects were also considered via the COSMO and C-PCM implicit models. Reasonable agreement was found between bond lengths and angle values in comparison with X-ray crystal structures. Relative equilibrium populations of different conformers were determined from molecular partition functions and the role of electronic, vibrational and rotational degrees of freedom on the stability of conformers were analyzed. For no level of theory is a zwitterionic structure stable in the gas-phase while solvation makes them available depending on the protonation state. Geometrically identified intramolecular hydrogen bonds were analyzed by QTAIM approach. All conformers exhibit strong inter-phosphonate hydrogen bonds and in most of them the alkyl-amine side chain is folded on the P-C-P backbone for further hydrogen bond formation.
Based on definition of angular central moments, a quantitative measure is proposed for comparativ... more Based on definition of angular central moments, a quantitative measure is proposed for comparative assessment of the anisotropy of different intermolecular potential energy surfaces at different intermolecular distances. Angular spreadness, skewness and peakedness are three features of anisotropy that are used here to describe the distribution of values of interaction energy around its isotropic component. In agreement with qualitative interpretations, the proposed measure exhibits a sharp change in the R-dependent pattern of anisotropy at an intermediate distance where the repulsive forces on the average overcome the attractive ones. The R-dependence of anisotropy of available N2–N2 potentials is examined in comparison with bare ab initio data and considerable discrepancies are found at distances shorter than the onset of repulsion. It is shown that the full experimentally derived potentials with simplified functional forms do not reproduce the correct anisotropy of interaction energy.
In this work, for the first time, an analytical four-dimensional representation for the intermole... more In this work, for the first time, an analytical four-dimensional representation for the intermolecular potential of the N(2)-CO dimer is constructed from ab initio calculations. The most stable structure of dimer is found to be a distorted T-shape conformation with CO forming the top and N(2) the leg of T. Important structures of the dimer are characterized, and surprisingly, it is found that in contrast with general assumptions, the potential energy surface of the N(2)-CO dimer has a single symmetry unique minimum. The energy profile of a minimum energy path that connects two T-shaped saddle points to the minimum structure is derived. Important structures are characterized along this path to represent the concerted internal rotation of monomers within the complex. The second virial coefficient is calculated from the fitted PES, and reasonable agreement is found with recent experimental results.
The intermolecular potential energy surface (PES) of the Cl2 dimer is calculated at the MP2/aTZ +... more The intermolecular potential energy surface (PES) of the Cl2 dimer is calculated at the MP2/aTZ + b level of ab initio theory. A quantitative measure is proposed for comparison of the anisotropy of PESs of different systems at different intermolecular distances. A high degree of anisotropy at short and intermediate distances results in the failure of fitting strategies that are based on the angular expansion of the potential energy. To tackle this problem, a step-by-step fitting strategy is designed for analytical representation of the PES. The global minimum energy configuration of the dimer is found to be a distorted L-shape structure with a well depth of around 615 cm−1. The PES is finally scaled to minimize deviations between calculated and experimental second virial coefficients.
Two analytical representations for the potential energy surface of the F2 dimer were constructed ... more Two analytical representations for the potential energy surface of the F2 dimer were constructed on the basis of ab initio calculations up to the fourth-order of Møller−Plesset (MP) perturbation theory. The best estimate of the complete basis set limit of interaction energy was derived for analysis of basis set incompleteness errors. At the MP4/aug-cc-pVTZ level of theory, the most stable structure of the dimer was obtained at R = 6.82 au, θa = 12.9°, θb = 76.0°, and φ = 180°, with a well depth of 716 μEh. Two other minima were found for canted and X-shaped configurations with potential energies around −596 and −629 μEh, respectively. Hexadecapole moments of monomers play an important role in the anisotropy of interaction energy that is highly R-dependent at intermediate intermolecular distances. The quality of potentials was tested by computing values of the second virial coefficient. The fitted MP4 potential has a more reasonable agreement with experimental values.
A recent N2–N2 potential has been used to calculate the second virial, viscosity, and diffusion c... more A recent N2–N2 potential has been used to calculate the second virial, viscosity, and diffusion coefficients. Calculations have been done up to the first quantum correction for virial coefficients and the second-order kinetic theory approximation for transport coefficients. The Mason–Monchick approximation (MMA) has been used for the calculation of collision integrals and, via a numerical analysis, a common intersection point has been found for reduced cross sections and collision integrals of different orientations. This regularity has been interpreted with the aim of the orientation dependence of the potential energy and different types of collisions between molecules. The overall agreement of the calculated second virial coefficient with experiment is reasonable but suggests that a slight re-scaling of the potential would be beneficial. In the case of transport properties, calculated and experimental results show an average deviation of about 1.6% and 0.7% for viscosity and relative diffusion coefficients, respectively.
A new four-dimensional potential energy surface has been developed for N2 dimer. Ab initio calcul... more A new four-dimensional potential energy surface has been developed for N2 dimer. Ab initio calculations were performed with the cc-pVXZ correlation consistent basis set. For calculating the PES of the N2 dimer, we have chosen to follow the supermolecular Møller–Plesset perturbation theory up to second order (MP2). Our MP2 results show that the most stable structure of N2 dimer is the slipped parallel form with θa = 50, θb = 50, phi = 0 conformation with 7.7 a.u. and 487.6 μH values of equilibrium distance and energy.
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Papers by Mohammad Hossein Karimi-Jafari
to characterize the conformational space of pamidronate,
a typical pharmaceutical for bone diseases. Mono-, diand
tri-protic states of molecule, relevant for physiological pH
range, were investigated for both canonical and zwitterionic
tautomers. Semiempirical PM6 method were used for prescreening
of the single bond rotamers followed by geometry
optimizations at the B3LYP/6-31++G(d,p) and B3LYP/6-
311++G(d,p) levels. For numerous identified low energy conformers
the final electronic energies were determined at the
MP2/6-311++G(2df,2p) level and corrected for thermal
effects at B3LYP level. Solvation effects were also considered
via the COSMO and C-PCM implicit models. Reasonable
agreement was found between bond lengths and angle values
in comparison with X-ray crystal structures. Relative equilibrium
populations of different conformers were determined
from molecular partition functions and the role of electronic,
vibrational and rotational degrees of freedom on the stability
of conformers were analyzed. For no level of theory is a
zwitterionic structure stable in the gas-phase while solvation
makes them available depending on the protonation state.
Geometrically identified intramolecular hydrogen bonds were
analyzed by QTAIM approach. All conformers exhibit strong
inter-phosphonate hydrogen bonds and in most of them the
alkyl-amine side chain is folded on the P-C-P backbone for
further hydrogen bond formation.
to characterize the conformational space of pamidronate,
a typical pharmaceutical for bone diseases. Mono-, diand
tri-protic states of molecule, relevant for physiological pH
range, were investigated for both canonical and zwitterionic
tautomers. Semiempirical PM6 method were used for prescreening
of the single bond rotamers followed by geometry
optimizations at the B3LYP/6-31++G(d,p) and B3LYP/6-
311++G(d,p) levels. For numerous identified low energy conformers
the final electronic energies were determined at the
MP2/6-311++G(2df,2p) level and corrected for thermal
effects at B3LYP level. Solvation effects were also considered
via the COSMO and C-PCM implicit models. Reasonable
agreement was found between bond lengths and angle values
in comparison with X-ray crystal structures. Relative equilibrium
populations of different conformers were determined
from molecular partition functions and the role of electronic,
vibrational and rotational degrees of freedom on the stability
of conformers were analyzed. For no level of theory is a
zwitterionic structure stable in the gas-phase while solvation
makes them available depending on the protonation state.
Geometrically identified intramolecular hydrogen bonds were
analyzed by QTAIM approach. All conformers exhibit strong
inter-phosphonate hydrogen bonds and in most of them the
alkyl-amine side chain is folded on the P-C-P backbone for
further hydrogen bond formation.