A full conformational space analysis of bilirubin

Hissi, Esteban Gabriel Vega; Martínez, Juan C. Garro; Zamarbide, Graciela N.; Estrada, Mario R.; Jensen, Svend J. Knak; Tomás-Vert, F; Csizmadia, Imre G.

doi:10.1016/j.theochem.2009.06.039

Cited by 8 publications

(5 citation statements)

References 24 publications

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“…Our systematic study includes a severe analysis of each fragment that was selected based on its chemical characteristics. Molecular fragmentation has been used in previous work of our group given excellent results in the study of large molecules (31,32).…”

Section: Resultsmentioning

confidence: 99%

In Silico Modeling of the Molecular Structure and Binding of Leukotriene A4 into Leukotriene A4 Hydrolase

et al. 2012

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A combined molecular docking and molecular structure in silico analysis on the substrate and product of leukotriene A4 hydrolase (LTA4H) was performed. The molecular structures of the substrate leukotriene A4 (LTA4) and product leukotirene B4 (LTB4) were studied through density functional theory (DFT) calculations at the B3LYP ⁄ 6-31 + G(d) level of theory in both gas and condensed phases. The whole LTB4 molecule was divided into three fragments (hydrophobic tail, triene motif, and a polar acidic group) that were subjected to a full conformational study employing the most stable conformations of them to build conformers of the complete molecule and geometry optimize further. LTA4 conformers' structures were modeled from the LTB4 minimum energy conformers. Both protonated and deprotonated species of LTA4 and LTB4 were analyzed according to pKa values found in the literature. Finally, a binding model of LTA4 with LTA4 hydrolase is proposed according to docking results that show intermolecular interactions that position the protonated and deprotonated ligand in the active site, in excellent agreement with the model suggested from LTA4H-inhibitors crystallographic data.Key words: binding, leukotriene A4 hydrolase, leukotrienes, molecular docking, molecular structure Received 3 April 2012, revised 12 July 2012 and accepted for publication 17 August 2012Leukotrienes (LTs) constitute a family of endogenous metabolites of arachidonic acid that are biosynthesized via the lipoxygenase pathway (1-3). These interesting compounds are a class of lipid mediators involved in the development and maintenance of inflammatory and allergic reactions (4-7). Leukotriene A4 (LTA4), an unstable alkyl epoxide formed from the immediate precursor 5-HPETE via 5-lipoxygenase (5-LO) (8), is converted to leukotriene B4 (5S,12R-dihydroxy-6Z,8E,10E,14Z-eicosatetraenoicacid; LTB4; Figure 1), by stereoselective hydratation of LTA4 hydrolase (LTA4H) (9). LTB4 is a potent proinflammatory mediator implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD), psoriasis, rheumatoid arthritis, and asthma and plays an important role in immunological responses, chronic obstructive pulmonary disease (COPD), and atherosclerosis (4,6,10-12).On the other hand, LTA4H is a bifunctional zinc metalloenzyme that catalyzes the rate-limiting step in the production of LTB4 (13). The X-ray crystal structures of LTA4H in complex with different inhibitors have been obtained by several authors (14-16). According to several investigations, the metal site is located next to the putative active site bound to His295, His299,.In this study, we show an analysis of the different interactions of LTA4 into LTA4H through molecular docking study. Molecular and electronic structure information of LTA4 and LTB4, obtained from an exhaustive conformational analysis, was used to set an initial conformation for the docking study.There are few theoretical studies about the molecular structure of LTB4. One of them was performed by Brasseur et al. (19) ...

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Section: Resultsmentioning

confidence: 99%

In Silico Modeling of the Molecular Structure and Binding of Leukotriene A4 into Leukotriene A4 Hydrolase

et al. 2012

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“…2 All bilirubin anionic species were generated by subtracting a proton (or two) from the neutral species. We carried out geometry optimizations in the gas-phase at B3LYP/6-31+G(d) 14,15 and MP2/6-31G(d) levels of theory.…”

Section: Methodsmentioning

confidence: 99%

“…1 This structure was also found to be the most stable one through quantum mechanical calculations. 2 The fact that these groups are not available to interact with water was used to explain the lipophilicity and poor water solubility of UCB. 3 In aqueous solutions UCB co-exists as three species in equilibrium, 4 the neutral diacid (H 2 B), the monoanions (HB − ), the structure of which differs only in the position of lactamic ring subtituents, and the dianion (B = ), with different properties and functions such as diffusion of the diacid through lipid membranes, like blood brain barrier, 5,6 binding of the monoanion to ABC-transporters, 5 and binding of the dianion to human serum albumin.…”

Section: Introductionmentioning

confidence: 99%

Computational chemical analysis of unconjugated bilirubin anions and insights into pKa values clarification

Vega-Hissi

Estrada

Lavecchia

et al. 2013

The Journal of Chemical Physics

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The pKa, the negative logarithm of the acid dissociation equilibrium constant, of the carboxylic acid groups of unconjugated bilirubin in water is a discussed issue because there are quite different experimental values reported. Using quantum mechanical calculations we have studied the conformational behavior of unconjugated bilirubin species (in gas phase and in solution modeled implicitly and explicitly) to provide evidence that may clarify pKa values because of its pathophysiological relevance. Our results show that rotation of carboxylate group, which is not restricted, settles it in a suitable place to establish stronger interactions that stabilizes the monoanion and the dianion to be properly solvated, demonstrating that the rationalization used to justify the high pKa values of unconjugated bilirubin is inappropriate. Furthermore, low unconjugated bilirubin (UCB) pKa values were estimated from a linear regression analysis.

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“…The chemistry and photophysics of bilirubin-related compounds were widely studied with static ab initio methods. The conformational sampling of bilirubin was studied several times in both the gas phase and solution. − A time-dependent DFT (TDDFT) method was used for the characterization of bilirubin excited states, absorption spectra, and the character of the photochemical intermediates. , Particular attention was paid to the excitonic coupling in these systems. − , Zietz and Blomngren have briefly analyzed the topography of the potential energy surface of a dipyrrinone model system finding a conical intersection attributed to the photoisomerization . Later, Garcı́a-Iriepa and co-workers calculated the analogous topography for a similar bilirubin model, benzalpyrrolinone, connecting it with the lifetimes from fs-TA spectroscopy mentioned above .…”

Section: Introductionmentioning

confidence: 99%

Conformational Control of the Photodynamics of a Bilirubin Dipyrrinone Subunit: Femtosecond Spectroscopy Combined with Nonadiabatic Simulations

et al. 2020

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The photochemistry of bilirubin has been extensively studied due to its importance in the phototherapy of hyperbilirubinemia. In the present work, we investigated the ultrafast photodynamics of a bilirubin dipyrrinone subunit, vinylneoxanthobilirubic acid methyl ester. The photoisomerization and photocyclization reactions of its (E) and (Z) isomers were studied using femtosecond transient absorption spectroscopy and by multireference electronic structure theory, where the nonadiabatic dynamics was modeled with a Landau−Zener surface hopping technique. The following picture has emerged from the combined theoretical and experimental approach. Upon excitation, dipyrrinone undergoes a very fast vibrational relaxation, followed by an internal conversion on a picosecond time scale. The internal conversion leads either to photoisomerization or regeneration of the starting material. Further relaxation dynamics on the order of tens of picoseconds was observed in the ground state. The nonadiabatic simulations revealed a strong conformational control of the photodynamics. The ultrafast formation of a cyclic photochemical product from a less-populated conformer of the studied subunit was predicted by our calculations. We discuss the relevance of the present finding for the photochemistry of native bilirubin. The work has also pointed to the limits of semiclassical nonadiabatic simulations for simulating longer photochemical processes, probably due to the zero-point leakage issue.

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A full conformational space analysis of bilirubin

Cited by 8 publications

References 24 publications

In Silico Modeling of the Molecular Structure and Binding of Leukotriene A4 into Leukotriene A4 Hydrolase

In Silico Modeling of the Molecular Structure and Binding of Leukotriene A4 into Leukotriene A4 Hydrolase

Computational chemical analysis of unconjugated bilirubin anions and insights into pKa values clarification

Conformational Control of the Photodynamics of a Bilirubin Dipyrrinone Subunit: Femtosecond Spectroscopy Combined with Nonadiabatic Simulations

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