MOLECULAR DYNAMICS STUDY OF THE AMA1 PROTEIN FROM PLASMODIUM FALCIPARUM AS A CANDIDATE FOR THE DEVELOPMENT OF ANTIMALARIAL VACCINES

Pamella Cristiny Carneiro da Silva; Leandro Martínez

Paper Title

Authors

Pamella Cristiny Carneiro da Silva
Leandro Martínez

Modality

Poster

Subject area

Proteins and Proteomics

Publishing Date

08/11/2023

Country of Publishing

Brazil | Brasil

Language of Publishing

Inglês

Paper Page

https://www.even3.com.br/anais/xmeeting2023/634884-molecular-dynamics-study-of-the-ama1-protein-from-plasmodium-falciparum-as-a-candidate-for-the-development-of-ant

ISBN

978-65-272-0061-1

Keywords

Molecular Dynamics, PfAMA1, IDPs, HREMD

Summary

Malaria is an endemic disease included in the group of neglected tropical diseases (NTDs). This work has as its main focus the Apical Membraine Antigen 1 (AMA1) of Plasmodium falciparum (PfAMA1), the main causative agent of lethal malaria cases. This is a surface protein found in more than one stage of the life cycle, acting on sporozoites and merozoites, closely related to parasitic invasion of erythrocytes and hepatocytes, respectively. Although its specific function is still poorly understood, it is known that it is a reorientation protein in the so-called “junction movement", the moment in which the parasite and host membranes are in close contact. Intrinsically Disordered Proteins (IDPs) are structurally heterogeneous proteins that can perform a biological function despite lacking well-defined and stable secondary and tertiary structural elements under physiological conditions. The residues of these proteins are highly flexible, have high levels of repeating regions and polarity, and contain little or no hydrophobic amino acids. The Plasmodium falciparum proteome is marked by a large number of IDPs, and therefore, there is a need to understand this class of proteins for an effective immune response. It is estimated that up to 70% of disease-associated genomes have at least 30 residues that present intrinsic disorder, justifying the interest in using IDPs as possible pharmacological targets. The structure of a conformational epitope in complex with an antibody was recovered from the PDB with the code 2J5L. This work used molecular dynamics methods of extended sampling Hamiltonian Replica Exchange Molecular Dynamics (HREMD) to understand mechanisms of interaction of PfAMA1 with the important antimalarial monoclonal antibody F8.12.19. HREMD allows accessing a greater conformational variability of a biomolecule, preventing the simulation from getting stuck in non-representative conformations in local minima of energy, something common in simulations of very flexible proteins due to the high degrees of freedom. Short simulations of 50 ns were performed to verify the exchange rates, and long simulations of 500 ns were performed where clustering methods were used to understand the most accessible conformations of the protein in the unbound state and in complex with the antibody. It was possible to observe, as indicated by the authors, that IDPs perform a combination of two interaction mechanisms: the lock and key followed by induced adjustment, where one of the metastable states binds to the partner protein, followed by the induced adjustment that is facilitated by the environment of the other protein. The simulated epitope alone in water accessed completely disordered conformations, something that was not observed in the trajectory in complex with the antibody. Also, Hydrogen bonds already observed experimentally were found in the complex interaction, as well as a more limited conformational variability. This shows the importance of the protein partner in the behavior of the IDPs, and although studies indicate high specificity and low affinity interactions, it is necessary to observe the interaction mechanism according to each protein.

Title of the Event: X-Meeting / BSB 2023
City of the Event: Curitiba
Title of the Proceedings of the event: X-Meeting presentations
Name of the Publisher: Even3
Means of Dissemination: Meio Digital

How to cite

SILVA, Pamella Cristiny Carneiro da; MARTÍNEZ, Leandro. MOLECULAR DYNAMICS STUDY OF THE AMA1 PROTEIN FROM PLASMODIUM FALCIPARUM AS A CANDIDATE FOR THE DEVELOPMENT OF ANTIMALARIAL VACCINES.. In: X-Meeting presentations. Anais...Curitiba(PR) Campus da indústria, 2023. Available in: https//www.even3.com.br/anais/xmeeting2023/634884-MOLECULAR-DYNAMICS-STUDY-OF-THE-AMA1-PROTEIN-FROM-PLASMODIUM-FALCIPARUM-AS-A-CANDIDATE-FOR-THE-DEVELOPMENT-OF-ANT. Access in: 31/08/2025