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Theoretical studies on cation-ligand interactions
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Type
Thesis
Author
Abirami Seduraman
Supervisor
Goh, Ngoh Khang
Ma, Ida N. L.
Abstract
In this thesis we have used the theoretical approach to quantify the interactions between H+/M+ with biologically important ligands and we have mainly focused to obtain the relative and absolute cation affinities of these species. We have also modelled the dissociation of cationized amino acids based on the mass spectrometry fragmentation.
Chapters 3 to 7 describe the various studies we have carried out to meet our objectives.
Chapter 3: In this chapter we have studied the interactions between the alkali metal cations and polyhydroxyl ligands. Ab initio molecular orbital calculations at the G3(GCP) level were conducted for the alkali cation-alcohol complexes ([M- L]+, where M+ = Li+, Na+, and K+; L = methanol, ethylene glycol, propan-1,2- diol, propan1,3-diol and propan-1,2,3-triol). In general, these cations maximize the number of M+...O interactions with the ligands. The roles of intramolecular hydrogen bonding, ligand polarizability, ligand deformations, number of M+...O interactions and the M+...O distances in governing [M-L]+ affinities were discussed. The computationally less expensive G2(MP2, SVP)–FC/ASC models were found to yield affinities in good agreement against the G3(GCP) benchmark, but the agreement deteriorates somewhat with increasing number of M+...O interactions.
Chapter 4: After investigating the effect of number of sites on structure and affinity, in this chapter we wish to look at the effect of chain length. We employed density functional theory to model the structure and the relative stabilities of α/βalanine conformers, and their protonated and alkali metal cationized complexes. In general, we find that the behavior of the β-alanine (β-Ala) system is quite similar to that of α-alanine (α-Ala). However, the presence of the methylene group (-CH2-) at the β position in β-Ala leads to a few key differences. Firstly, the intramolecular hydrogen bonding patterns are different between free α- and β-Ala. Secondly, the stability of zwitterionic species (in either the free ligand or alkali metal cationized complexes) is often enhanced in β-Ala. Thirdly, the preferred mode of alkali metal cation (M+) binding may also differ in α- and β-Ala. Natural Energy Decomposition Analysis has been applied here to gain further insight into the effects of the ligand, cation size and mode of binding on the nature of interaction in these [M-Ala]+ complexes.
Chapter 5: In this chapter we have explored the interaction between potassium cation (K+) and proline- containing dipeptides, prolylglycine (PG) and glycylproline (GP). We found that prolylglycine and its potassiated complexes [K-PG]+ closely resemble those of the analogous glycylglycine (GG) and its potassiated complexes [KGG]+ reported previously. For glycylproline (GP), the nitrogen being a part of the pyrrolidine ring, its structures, relative stabilities of conformers, and the preferred mode of K+ binding are different from those of prolylglycine (PG) and glycylglycine (GG). Our study suggests that even though replacing glycine with a proline residue enhances the stability of the zwitterionic mode of binding, the most stable mode of K+ binding remains to be charge-solvated in nature in both PG (K+ doubly coordinated to amide and C-terminal carbonyl oxygens) and GP (K+ triply coordinated to amide oxygen, C-terminal carbonyl oxygen and N-terminal amino nitrogen), and the K+ affinities estimated for PG and GP are 154 and 159 kJ mol-1, respectively.
Chapter 6: With the factors affecting the structures and affinity understood, we hope to establish theoretical methods that can model the reaction of cation-ligand ions in the gas phase. In this chapter, we have modelled the fragmentation of protonated aliphatic amino acids (glycine, alanine and valine,). The potential energy surface for the competitive fragmentation leading to the loss of CO, H2O and (CO + H2O) is studied theoretically. We found that the preference of the formation of (CO + H2O) over CO in the larger aliphatic amino acid arises from two factors. Firstly, additional methyl group on alanine and valine stabilizes the corresponding immonium cation associated with the loss of (CO + H2O), through hyperconjugation. Secondly, as more fragments are produced, the entropy factor also favors the formation of (CO + H2O) over CO. Furthermore, our study offers an alternative explanation to the noncompetitive formation of H2O over loss of CO, (CO + H2O) in protonated aliphatic amino acid.
Chapter 7: It has been found experimentally that the dissociation product from the protonated alanine is different from that of alkaliated alanine. It is interesting to note that dissociation channel shows metal dependence. In this chapter, the dissociation of a prototypical metal cationized amino acid complex, alkaliated alanine ([Ala + M]+, where M+ = Li+, Na+ and K+), has been studied by energy-resolved tandem mass spectrometry using an ion trap mass analyzer, and density functional theory. The dissociation leads to formation of fragment ions arising from loss of small neutrals such as H2O, CO, NH3 and (CO + NH3). The order of appearance threshold voltages for different dissociation pathways determined experimentally is consistent with the order of critical energies (energy barriers) obtained theoretically, thus providing the necessary confidence to both the experimental and theoretical results.
Despite not explicitly involved in the reaction, the alkali metal cation plays novel and important roles in the dissociation of alkaliated alanine. The metal cation not only catalyses the dissociation (via the formation of loosely bound ion-molecule complexes and by stabilizing the more polar intermediates and transition structures), the dissociation mechanisms are also affected as the cation can alter the shape of the potential energy surfaces. This compression/expansion of the potential energy surface as a function of the alkali metal cation is discussed in detail, and how this affects the competitive loss of H2O versus CO/(CO + NH3) from [Ala + M]+ is illustrated. The study provides new insights into the origin of the competition between various dissociation channels of alkaliated amino acid complexes.
Chapters 3 to 7 describe the various studies we have carried out to meet our objectives.
Chapter 3: In this chapter we have studied the interactions between the alkali metal cations and polyhydroxyl ligands. Ab initio molecular orbital calculations at the G3(GCP) level were conducted for the alkali cation-alcohol complexes ([M- L]+, where M+ = Li+, Na+, and K+; L = methanol, ethylene glycol, propan-1,2- diol, propan1,3-diol and propan-1,2,3-triol). In general, these cations maximize the number of M+...O interactions with the ligands. The roles of intramolecular hydrogen bonding, ligand polarizability, ligand deformations, number of M+...O interactions and the M+...O distances in governing [M-L]+ affinities were discussed. The computationally less expensive G2(MP2, SVP)–FC/ASC models were found to yield affinities in good agreement against the G3(GCP) benchmark, but the agreement deteriorates somewhat with increasing number of M+...O interactions.
Chapter 4: After investigating the effect of number of sites on structure and affinity, in this chapter we wish to look at the effect of chain length. We employed density functional theory to model the structure and the relative stabilities of α/βalanine conformers, and their protonated and alkali metal cationized complexes. In general, we find that the behavior of the β-alanine (β-Ala) system is quite similar to that of α-alanine (α-Ala). However, the presence of the methylene group (-CH2-) at the β position in β-Ala leads to a few key differences. Firstly, the intramolecular hydrogen bonding patterns are different between free α- and β-Ala. Secondly, the stability of zwitterionic species (in either the free ligand or alkali metal cationized complexes) is often enhanced in β-Ala. Thirdly, the preferred mode of alkali metal cation (M+) binding may also differ in α- and β-Ala. Natural Energy Decomposition Analysis has been applied here to gain further insight into the effects of the ligand, cation size and mode of binding on the nature of interaction in these [M-Ala]+ complexes.
Chapter 5: In this chapter we have explored the interaction between potassium cation (K+) and proline- containing dipeptides, prolylglycine (PG) and glycylproline (GP). We found that prolylglycine and its potassiated complexes [K-PG]+ closely resemble those of the analogous glycylglycine (GG) and its potassiated complexes [KGG]+ reported previously. For glycylproline (GP), the nitrogen being a part of the pyrrolidine ring, its structures, relative stabilities of conformers, and the preferred mode of K+ binding are different from those of prolylglycine (PG) and glycylglycine (GG). Our study suggests that even though replacing glycine with a proline residue enhances the stability of the zwitterionic mode of binding, the most stable mode of K+ binding remains to be charge-solvated in nature in both PG (K+ doubly coordinated to amide and C-terminal carbonyl oxygens) and GP (K+ triply coordinated to amide oxygen, C-terminal carbonyl oxygen and N-terminal amino nitrogen), and the K+ affinities estimated for PG and GP are 154 and 159 kJ mol-1, respectively.
Chapter 6: With the factors affecting the structures and affinity understood, we hope to establish theoretical methods that can model the reaction of cation-ligand ions in the gas phase. In this chapter, we have modelled the fragmentation of protonated aliphatic amino acids (glycine, alanine and valine,). The potential energy surface for the competitive fragmentation leading to the loss of CO, H2O and (CO + H2O) is studied theoretically. We found that the preference of the formation of (CO + H2O) over CO in the larger aliphatic amino acid arises from two factors. Firstly, additional methyl group on alanine and valine stabilizes the corresponding immonium cation associated with the loss of (CO + H2O), through hyperconjugation. Secondly, as more fragments are produced, the entropy factor also favors the formation of (CO + H2O) over CO. Furthermore, our study offers an alternative explanation to the noncompetitive formation of H2O over loss of CO, (CO + H2O) in protonated aliphatic amino acid.
Chapter 7: It has been found experimentally that the dissociation product from the protonated alanine is different from that of alkaliated alanine. It is interesting to note that dissociation channel shows metal dependence. In this chapter, the dissociation of a prototypical metal cationized amino acid complex, alkaliated alanine ([Ala + M]+, where M+ = Li+, Na+ and K+), has been studied by energy-resolved tandem mass spectrometry using an ion trap mass analyzer, and density functional theory. The dissociation leads to formation of fragment ions arising from loss of small neutrals such as H2O, CO, NH3 and (CO + NH3). The order of appearance threshold voltages for different dissociation pathways determined experimentally is consistent with the order of critical energies (energy barriers) obtained theoretically, thus providing the necessary confidence to both the experimental and theoretical results.
Despite not explicitly involved in the reaction, the alkali metal cation plays novel and important roles in the dissociation of alkaliated alanine. The metal cation not only catalyses the dissociation (via the formation of loosely bound ion-molecule complexes and by stabilizing the more polar intermediates and transition structures), the dissociation mechanisms are also affected as the cation can alter the shape of the potential energy surfaces. This compression/expansion of the potential energy surface as a function of the alkali metal cation is discussed in detail, and how this affects the competitive loss of H2O versus CO/(CO + NH3) from [Ala + M]+ is illustrated. The study provides new insights into the origin of the competition between various dissociation channels of alkaliated amino acid complexes.
Date Issued
2006
Call Number
QP517.L54 Abi
Date Submitted
2006