Extended conformational selection: molecular dynamics of the PfAMA1 antigen-antibody interaction mechanism

The Plasmodium falciparum Apical Membrane Antigen 1 protein (PfAMA1), is a surface protein found in more than one stage of the malaria life cycle. It is a reorientation protein in the so-called “junction movement”, the moment when the membranes of the parasite and the host are in contact during invasion. The structure of a conformational epitope of domain III of PfAMA1 in complex with the monoclonal antibody Fab F8.12.19 is experimentally known, and this work used a enhanced sampling method by Hamiltonian Replica Exchange Molecular Dynamics (HREMD) to understand the effect of intermolecular interactions, conformational variability, and intrinsically disordered regions on the mechanism of antigen-antibody interaction. Clustering methods and conformational analyzes were used in order to understand more accessible conformations and the influence of the presence or absence of the partner protein in the complex interaction. The free-state epitope accesses a broader conformational pool including fully disordered conformations not observed in the bound state. From Molecular Dynamics it was possible to describe the extended conformational selection mechanism, in which the antibody interacted and stabilized an already existing epitope conformation in free state. The stabilization of the active conformation occurs mainly by hydrogen bonds: Tyr(H33)-Asp493, Tyr(H35)-Asp493 and His(L94)-Val510. Although the antibody is a rigid structure, the presence of the epitope induced small adjustments in the complementarity determining regions (CDR), the exception to this behavior is CDR-H3 which has a greater variability known in the literature. This shows the importance of partner protein and intermolecular interactions to understand the influence of disordered regions on epitopes with vaccine potential.