The urokinase plasminogen activator binding to its receptor: a quantum biochemistry description within an in/homogeneous dielectric function framework with application to uPA-uPAR peptide inhibitors

Autor(es)

Morais, Pablo A. ^[1] ; Maia, Jr., Francisco Francine ^[2] ; Solis-Calero, Christian ^[3] ; Santos Caetano, Ewerton Wagner ^[4] ; Freire, Valder Nogueira ^[5] ; Carvalho, Hernandes F. ^[3]

Afiliação do(s) autor(es)

^[1] Inst Fed Educ Ciencia & Tecnol Ceara, Campus Horizonte, Horizonte, CE - Brazil

^[2] Univ Fed Rural Semi Arido, Dept Ciencias Nat Matemat & Estat, Mossoro, RN - Brazil

^[3] Univ Estadual Campinas, Inst Biol, Dept Biol Estrutural & Func, Campinas, SP - Brazil

^[4] Inst Fed Educ Ciencia & Tecnol Ceara, Fortaleza, CE - Brazil

^[5] Univ Fed Ceara, Dept Fis, Fortaleza, CE - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Physical Chemistry Chemical Physics; v. 22, n. 6, p. 3570-3583, FEB 14 2020.
• Citações Web of Science: 0

Resumo

Despite being recognized as a therapeutic target in the processes of cancer cell proliferation and metastasis for over 50 years, the interaction of the urokinase plasminogen activator uPA with its receptor uPAR still needs an improved understanding. High resolution crystallographic data (PDB 2FD6) of the uPA-uPAR binding geometry was used to perform quantum biochemistry computations within the density functional theory (DFT) framework. A divide to conquer methodology considering a mixed homogeneous/inhomogeneous dielectric model and explicitly taking water molecules into account was employed to obtain a large set of uPA-uPAR residue-residue interaction energies. In order of importance, not only were Phe25 > Tyr24 > Trp30 > Ile28 shown to be the most relevant uPA residues binding it to uPAR, but the residues Lys98 > His87 > Gln40 v Asn22 > Lys23 > Val20 also had significant interaction energies, which helps to explain published experimental mutational data. Furthermore, the results obtained with the uPA-uPAR in/homogeneous dielectric function show that a high dielectric constant value epsilon = 40 is adequate to take into account the electrostatic environment at the interface between the proteins, while using a smaller value of epsilon (<10) leads to an overestimation of the uPA-uPAR binding energy. Hot spots of the uPA-uPAR binding domain were identified and a quantum biochemistry description of the uPAR blockers uPA(21 30) and cyclo(21,29)uPA(21-29){[}(S21C;H29C)] was performed, demonstrating that cyclization improves the stability of mimetic peptides without compromising their binding energies to uPAR. (AU)

• Processo FAPESP: 14/50938-8 - INCT 2014: em Fotônica Aplicada à Biologia Celular INFABiC
• Beneficiário: Hernandes Faustino de Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 09/16150-6 - Regulação androgênica, sinalização e interações celulares no desenvolvimento, fisiologia e regressão prostática
• Beneficiário: Hernandes Faustino de Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Temático