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Relationship between obesity and the TLR4 receptor: New studies by molecular dynamics simulations

Grant number: 12/24750-6
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): May 01, 2013
Effective date (End): April 30, 2016
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Physical-Chemistry
Principal Investigator:Munir Salomao Skaf
Grantee:Paulo Cesar Telles de Souza
Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated scholarship(s):14/22007-0 - Coarse-graining molecular dynamics simulations of TLR4 complexes, BE.EP.PD


Obesity is a medical condition resulting from the loss on the balance between food intake and energy expenditure. It predisposes the organism to various other illnesses, such as cardiovascular disease and diabetes mellitus type 2, and it is currently considered one of the ten major public health problems in the world. New studies have shown that diets high in animal fat can cause inflammation in the hypothalamus that lead to loss of the ability of the control of feeding and energy expenditure, and thus obesity. It was observed that these inflammations are due to an saturated fatty acids association to a receptor of the innate immune system, the TLR4, belonging to a family of transmembrane proteins known as toll-like receptors (TLR) . TLRs are responsible for the molecular recognition of pathogens expressed by infectious agents, which triggers a cascade of events that lead to inflammation. The TLR4 is responsible for recognizing lipopolysaccharide, essential components of the Gram-negative bacteria outer membrane. Little is known about the molecular mechanisms involved in interactions between saturated fatty acids and TLR4 that allow these biomolecules act as agonists, activating the function of TLR4 and thus leading to inflammation. Furthermore, the mechanisms by which ligands such as Lipid IVa and Eritoran can act with TLR4 antagonist, whereas Lipid A acts as an agonist, are not understood yet. In this project, we intend to apply molecular dynamics (MD) simulation techniques to study interactions between different ligands and TLR4 in order to elucidate the molecular reasons of agonists and antagonists action of these ligands. We seek to provide unprecedented information at the molecular level to deepen studies that have been developed by the group of Prof. Dr. Licio A. Veloso, Faculty of Medical Sciences, UNICAMP, who is co-supervising this project. Initially, the main objective of the research will focus on studies of the structure, dynamics and interactions between TLR4 and the agonist Lipid A, starting from crystallographic structures available in the literature. This first step will be followed by molecular modeling studies of the saturated fatty acids (with 16 to 18 carbons) binding modes, since there is still no crystallographic structures of these complexes. We also propose to study the molecular ratios of antagonism actions of Lipid IVa and Eritoran, by comparing the results of MD simulations carried out with these ligands and with Lipid A. Finally, we propose the molecular modeling of a mutant TLR4 (P712H). This mutant receptor is recognized by its low activity and therefore cause obesity in animal models. A better understanding of the antagonism actions of certain ligands and structural changes caused by mutations can contribute to the development of drugs that act in TLR4 for the obesity treatment or even acute inflammations such as sepsis. We also point out that this project establishes the beginning of a collaboration between two CEPIDs recently approved by FAPESP, Obesity and Co-morbidities Research Center (Proc. 2011/51349-8), coordinated by Prof. Lício Velloso, and the Center for Computational Engineering and Sciences (Proc. 2011/51348-1), coordinated by Prof. Munir Skaf.

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Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ZANOTTO, LEANDRO; HEERDT, GABRIEL; SOUZA, PAULO C. T.; ARAUJO, GUIDO; SKAF, MUNIR S.. High performance collision cross section calculationHPCCS. Journal of Computational Chemistry, v. 39, n. 21, p. 1675-1681, . (13/08293-7, 16/04963-6, 12/24750-6)
CAJAHUARINGA, SAMUEL; ZANOTTO, LEANDRO N.; CAETANO, DANIEL L. Z.; RIGO, SANDRO; YVIQUEL, HERVE; SKAF, MUNIR S.; ARAUJO, GUIDO; IEEE COMP SOC. Ion-Molecule Collision Cross-Section Simulation using Linked-cell and Trajectory Parallelization. 2022 IEEE 34TH INTERNATIONAL SYMPOSIUM ON COMPUTER ARCHITECTURE AND HIGH PERFORMANCE COMPUTING (SBAC-PAD 2022), v. N/A, p. 10-pg., . (12/24750-6, 16/04963-6, 13/08293-7, 21/03224-3, 19/19662-0)
MOTTIN, MELINA; SOUZA, PAULO C. T.; SKAF, MUNIR S.. Molecular Recognition of PPAR gamma by Kinase Cdk5/p25: Insights from a Combination of Protein-Protein Docking and Adaptive Biasing Force Simulations. Journal of Physical Chemistry B, v. 119, n. 26, p. 8330-8339, . (13/08293-7, 11/22735-7, 12/24750-6)
MOTTIN, MELINA; SOUZA, PAULO C. T.; RICCI, CLARISSE G.; SKAF, MUNIR S.. CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor gamma Ligands. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 18, n. 1, . (12/24750-6, 11/22735-7, 13/08293-7)
SOUZA, PAULO C. T.; TEXTOR, LARISSA C.; MELO, DENISE C.; NASCIMENTO, ALESSANDRO S.; SKAF, MUNIR S.; POLIKARPOV, IGOR. An alternative conformation of ER beta bound to estradiol reveals H12 in a stable antagonist position. SCIENTIFIC REPORTS, v. 7, . (13/08293-7, 14/22007-0, 12/24750-6)

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