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Molecular dynamics simulations of proton dependent oligopeptide transporters

Grant number: 16/16328-3
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): April 01, 2017
Effective date (End): March 31, 2020
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Antonio José da Costa Filho
Grantee:Mariana Raquel Bunoro Batista
Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Peptide transport into the cells plays an important role in cellular homeostase and is one of the main route through which the organisms absorb nitrogen. This mechanism is conserved across all organisms from bacteria to higher animals and plants. Proteins involved in peptide uptake and transport belong to the proton-coupled oligopeptide transporter (POT) family. A common feature of POT family transporters is its ability to recognize and transport a wide variety of substrates. These proteins are involved in the transport of more than 8000 different types of di- and tripeptides, including peptide-like drugs. The question of how a singlebinding site can recognize a variety of substrates is a major focus in peptide transport research. Structural studies combined with biophysical analyses have recently shown that these proteins interact differently with di- and tripeptides. While dipeptides bind in a horizontal position with respect to the plane of the membrane, tripeptides adopt a verticalorientation and make different interactions within the binding site. In addition, these studies have also demonstrated that different binding modes are associated with thermodynamically distinct transport mechanism. These mechanisms operate at two distinct rates and require different number of protons, depending onthe size of the peptides transported. Although these results suggest the existence of two distinct transport mechanisms, whichoperate from the same binding site, the molecular basis for this observation is still unknown. In this project, we aim to apply atomistic molecular dynamic simulations to study the effect of the proton motive force (pmf) onstructure and dynamic of PepTSo and PepTSt transporters in a lipid bilayer. Enhanced sampling molecular dynamics methods will be used to describe intermediate states of transport process. Coarse-grained models will be used to investigate the effect of different classes lipid classes on the dynamic of these transporters. This proposal os a fundamental part of the bilateral grant FAPESP/RCUK/BBSRC (Fapesp Proc. 2015/50366-7). In this grant, we intend to investigate the mechanistic details of peptide transport across membranes via a combined experimental-theoretical approach. This will be achieved through a collaboration involving our group and the group of Prof. Dr. Anthony Watts (University of Oxford). (AU)

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Scientific publications
(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)
KAVA, EMANUEL; MENDES, LUIS F. S.; BATISTA, MARIANA R. B.; COSTA-FILHO, ANTONIO J.. Myristoylation and its effects on the human Golgi Reassembly and Stacking Protein 55. Biophysical Chemistry, v. 279, . (15/50366-7, 16/16328-3, 17/24669-8, 12/20367-3)
BATISTA, MARIANA R. B.; WATTS, ANTHONY; COSTA-FILHO, ANTONIO JOSE. Exploring Conformational Transitions and Free-Energy Profiles of Proton-Coupled Oligopeptide Transporters. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, v. 15, n. 11, p. 6433-6443, . (16/16328-3, 15/50366-7)
MENDES, LUIS F. S.; BATISTA, MARIANA R. B.; KAVA, EMANUEL; BLEICHER, LUCAS; MICHELETTO, MARIANA C.; COSTA-FILHO, ANTONIO J.. Resurrecting Golgi proteins to grasp Golgi ribbon formation and self-association under stress. International Journal of Biological Macromolecules, v. 194, p. 264-275, . (16/16328-3, 15/16812-0, 15/50366-7, 12/20367-3, 18/13016-6, 17/24669-8)

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