CARNITINE PALMITOYL TRANSFERASE I: CONFORMATIONAL CHANGES INDUCED BY COA DERIVATES LIGANDS

Vitor Galvão Lopes; Marcos Yukio Yoshinaga; Mario Hiroyuki Hirata; Glaucio Monteiro Ferreira

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Submission

Paper Title

CARNITINE PALMITOYL TRANSFERASE I: CONFORMATIONAL CHANGES INDUCED BY COA DERIVATES LIGANDS

Authors

Vitor Galvão Lopes
Marcos Yukio Yoshinaga
Mario Hiroyuki Hirata
Glaucio Monteiro Ferreira

Modality

Xpress presentation

Subject area

Structural Bioinformatics

Publishing Date

26/04/2022

Country of Publishing

Brasil

Language of Publishing

Inglês

Paper Page

https://www.even3.com.br/anais/xmeetingxp2021/409908-carnitine-palmitoyl-transferase-i--conformational-changes-induced-by-coa-derivates-ligands

ISBN

978-65-5941-645-5

Keywords

Carnitine palmitoyl transferase I, Molecular dynamics, Long-chain fatty acids, apostructure

Summary

The Carnitine Palmitoyltranferase I (CPT1) catalyzes the rate-limiting step of long-chain fatty acid (LCFA) ß-oxidation. The enzyme promotes the conjugation of LCFA with L-carnitine, which allows the LCFA entry into the mitochondria matrix. The structural features involved in CPT1 and CoA-derivatives interactions have not been elucidated, mainly due to the absence of crystallographic data of CPT1. Previous studies reported the importance of study the CPT11,2, and nonetheless, these studies have not explored the LCFA bindings. We aimed to understand by molecular modeling strategies the conformational changes induced by CoA derivates. Hence, the tridimensional L-CPT1 model was built by homology modeling using CRAT protein (PBD:1t7q, resolution 1.8 Å)3 as a template. We simulated the CPT1 structure in the presence of CoA-derivatives and the absence of the ligands by molecular dynamics (MD). As a result, the principal component analysis (PCA) suggested the two states of apostructure CPT1 based on CoA-Loop (688-711) extreme motions than in the presence of the CoA-LCFA derivates. Simultaneously, the ligand-complexed simulations present one state and smaller conformational subspaces. The CoA moiety of ligands interacts with charged residues, namely Lys560, Lys556, Arg563, and Arg645. The frequency of interactions observed in each of those residues is < 60% of simulation time. It suggests a dynamic profile of interactions, which occurs in synergy with long-carbon chain interactions over a-I (478-492). These features may be associated with the adoption of LCFA to catalytic conformation. In order to free energy analysis, we observed that the alpha derivate increased the energy value (-79.2 Kcal.mol-1) along with the simulation than gamma (-69.3 Kcal.mol-1) and arachidonic (-69.1 Kcal.mol-1). In conclusion, the present structural model and simulations provide molecular-level insight into LCFA and L-CPT1 interactions, besides the structural features related to the binding free energy profile. Further, these findings may help the comprehension of the conformations induced by CoA derivates.

Title of the Event: X-Meeting XPerience 2021
Title of the Proceedings of the event: X-Meeting presentations
Name of the Publisher: Even3
Means of Dissemination: Meio Digital

How to cite

LOPES, Vitor Galvão et al.. CARNITINE PALMITOYL TRANSFERASE I: CONFORMATIONAL CHANGES INDUCED BY COA DERIVATES LIGANDS.. In: X-Meeting presentations. Anais...São Paulo(SP) AB3C, 2021. Available in: https//www.even3.com.br/anais/xmeetingxp2021/409908-CARNITINE-PALMITOYL-TRANSFERASE-I--CONFORMATIONAL-CHANGES-INDUCED-BY-COA-DERIVATES-LIGANDS. Access in: 29/04/2025