Molecular Orbital Calculations on the Interaction of Veratryl Alcohol with the Lignin Peroxidase Active Site

1999 ◽  
pp. 186-204 ◽  
Author(s):  
Thomas Elder ◽  
David C. Young
Keyword(s):  
Molecular Orbital ◽  
Lignin Peroxidase ◽  
Active Site ◽  
Veratryl Alcohol ◽  
Molecular Orbital Calculations

scholarly journals Interactive design and synthesis of a novel antibacterial agent

1994 ◽  
Vol 72 (4) ◽  
pp. 1051-1065 ◽  
Author(s):  
Saul Wolfe ◽  
Haolun Jin ◽  
Kiyull Yang ◽  
Chan-Kyung Kim ◽  
Ernest McEachern
Keyword(s):  
Molecular Orbital ◽  
Active Site ◽  
Antibacterial Agent ◽  
De Novo ◽  
Three Dimensional ◽  
Hydroxyl Group ◽  
Molecular Orbital Calculations ◽  
Binding Studies ◽  
Molecular Mechanics Calculations ◽  
Substrate Complex

β-Lactam compounds act on penicillin-recognizing enzymes via acylation of the hydroxyl group of an active site serine. When the resulting acyl enzyme is kinetically stable, as in the case of a penicillin-binding protein (PBP), the biosynthesis of a bacterial cell wall is inhibited, and death of the organism results. The de novo design of an antibacterial agent targeted to a PBP might be possible if the three-dimensional structural requirements of the equilibrium (i.e, fit) and catalytic (i.e. reactivity) steps of the aforementioned enzymatic process could be determined. For a model of the active site of a PBP from Streptomyces R61, the use of molecular mechanics calculations to treat "fit," and ab initio molecular orbital calculations to treat "reactivity," leads to the idea that the carboxyl group (G1) and the amide N-H (G2) of the antibiotic are hydrogen bonded to a lysine amino group and a valine carbonyl group in the enzyme–substrate complex. These two hydrogen bonds place the serine hydroxyl group on the convex face of the antibiotic, in position for attack on the β-lactam ring by a neutral reaction, catalyzed by water, that involves a direct proton transfer to the β-lactam nitrogen. Molecular orbital calculations of structure–reactivity relations associated with this mechanism suggest that C=N is bioisosteric to the β-lactam N-C(=O), comparable to a β-lactam in its reactivity with an alcohol, and that the product RO(C-N)H is formed essentially irreversibly (−ΔE > 10 kcal/mol). Accordingly, structures containing a G1 and a G2 separated by a C=N, and positioned in different ways with respect to this functional group, have been synthesized computationally and examined for their ability to fit to the PBP model. This strategy identified a 2H-5,6-dihydro-1,4-thiazine substituted by hydroxyl and carboxyl groups as a target for chemical synthesis. However, exploratory experiments suggested that the C=N of this compound equilibrates with endocyclic and exocyclic enamine tautomers. This required that the C2 position be substituted, and that the hydroxyl group not be attached to the carbon atom adjacent to the C=N. These conditions are met in a 2,2-dimethyl-3-(2-hydroxypropyl)-1,4-thiazine, which also exhibits the necessary fit to the PBP model. Two epimers of this compound have been synthesized, from D- and L-serine. The compound derived from L-serine is not active. The compound derived from D-serine exhibits antibacterial activity, but is unstable, and binding studies with PBP's have not been performed. It is hoped that these studies can be carried out if modification of the lead structure leads to compounds with improved chemical stability.

Molecular Orbital Studies of Enzyme Catalysed Reactions. Rearrangement of Chorismate to Prephenate

1979 ◽  
Vol 32 (9) ◽  
pp. 1921 ◽  
Author(s):  
PR Andrews ◽  
RC Haddon
Keyword(s):  
Aqueous Solution ◽  
Transition State ◽  
Molecular Orbital ◽  
Active Site ◽  
Active Sites ◽  
Transition States ◽  
Reaction Pathways ◽  
Carboxyl Groups ◽  
Molecular Orbital Calculations ◽  
Charge Delocalization

Molecular orbital calculations are used to describe the reaction surface for the non-enzymic Claisen rearrangement of chorismate to prephenate, which may proceed through either a boat-like or a chair-like transition state. Detailed molecular geometries are obtained for the neutral and dianionic forms of chorismate, prephenate, and the alternative transition states. The transition states are asymmetric structures in which the breaking C-O bond (c. 1.45 A) is significantly shorter than the making C-C bond (c. 1.95 A). The alternative reaction pathways have almost identical enthalpies of activation (chair, 277.4 kJ/mol ; boat, 282.8 kJ/mol; dianionic forms) which result partly from a loss of internal bond strength and partly from repulsive interactions between the polar carboxyl groups. Protonation stabilizes the transition states (chair, 247.3 kJ/mol; boat, 248.5 kJ/mol ; diacid forms) by delocalization of charge in the carboxyl groups, and a similar mechanism is proposed for the greatly reduced enthalpy of activation in aqueous solution (86.6 kJ/mol). The enthalpy difference between the alternative reaction pathways is insufficient to define a preferred transition state structure, and either pathway may be favoured for the non-enzymic reaction in aqueous solution. For the enzyme-catalysed reaction the chair pathway is used, and the calculated transition state structures and enthalpy barriers provide information relevant to the catalytic mechanism. They indicate that an active site comprising only two essential binding groups is sufficient to account for catalysis; the orientation of these groups within the active site should allow simultaneous bond formation, accompanied by charge delocalization, to both carboxyl groups of the transition state, but not to those of substrate or product. The calculated structure for the chair transition state, taken in conjunction with those for chorismate and prephenate, thus provides a template for the active sites of chorismate mutases.

Interactions between Methylene Blue and Pullulan According to Molecular Orbital Calculations

2020 ◽  
Vol 140 (11) ◽  
pp. 529-533
Author(s):  
Pasika Temeepresertkij ◽  
Saranya Yenchit ◽  
Michio Iwaoka ◽  
Satoru Iwamori
Keyword(s):  
Methylene Blue ◽  
Molecular Orbital ◽  
Molecular Orbital Calculations
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