title: Investigating the differential activation of vascular endothelial growth factor (VEGF) receptors.
abstract: The vascular endothelial growth factors are key mediators of angiogenesis and are also related to several physiological processes such as monocyte chemotaxis, dendritic cell development, hematopoietic stem cell survival, and many others. PlGF, VEGF, VEGFB, VEGFC and VEGFD were identified as members of the vascular endothelial growth factor family. They act by differential activation of three receptors: Flt-1, KDR and Flt-4. PlGF and VEGFB only activate Flt-1. VEGF activates both Flt-1 and KDR. VEGFC and VEGFD activate KDR and Flt-4. The available three dimensional structures of VEGF and PlGF, in complex with the domain-2 of Flt-1, show that both proteins bind in a very similar way to Flt-1 receptor. Here we construct the three dimensional model of the domain-2 of KDR receptor using the same domain of Flt-1 as template. We also construct the model complexes VEGF/KDR, VEGFB/Flt-1, VEGFB/KDR and PlGF/KDR. Molecular dynamics simulations with explicit solvent are carried out on eleven molecular systems: unbound VEGF, VEGF/Flt-1(D2), VEGF/KDR(D2), unbound PlGF, PlGF/Flt-1(D2), PlGF/KDR(D2), unbound VEGFB, VEGFB/Flt-1(D2), VEGFB/KDR(D2), unbound Flt-1(D2) and unbound KDR(D2). We analyze protein-protein interactions, shape complementarity, charge complementarity and hydrogen bonds. As a coarse estimation of the desolvation penalties, we assume a correlation to the number of hydrogen bonds with solvent molecules that are lost upon complex formation. The results herein are consistent with the experimental selectivity profile (VEGF being able to activate both Flt-1 and KDR receptors while VEGFB and PlGF being only able to activate Flt-1), and provide a collection of evidences sustaining the complementarity of polar interactions as the main responsible for protein recognition and selectivity.
authors.affiliation: Physical Organic Chemistry Group, Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, CT, Bloco A, lab. 609, Rio de Janeiro, RJ 21941-909, Brazil. bruno.horta@igc.phys.chem.ethz.ch
authors.forename: Bruno Araújo Cautiero
authors.initials: BA
authors.lastname: Horta
authors.forename: Ana Carolina Rennó
authors.initials: AC
authors.lastname: Sodero
authors.forename: Ricardo Bicca
authors.initials: RB
authors.lastname: de Alencastro
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D040262:Receptors, Vascular Endothelial Growth Factor / Q000737:chemistry* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000737:chemistry / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3