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

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 )...

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Bibliographic Details
Published in:Physical chemistry chemical physics : PCCP 2020-02, Vol.22 (6), p.357-3583
Main Authors: Morais, Pablo A, Maia, Francisco Franciné, Solis-Calero, Christian, Caetano, Ewerton Wagner Santos, Freire, Valder Nogueira, Carvalho, Hernandes F
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acids - chemistry
Binding energy
Biochemistry
Crystallography
Density Functional Theory
Peptides
Peptides, Cyclic - chemistry
Protein Binding
Protein Conformation
Receptors, Urokinase Plasminogen Activator - chemistry
Residues
Static Electricity
Structure-Activity Relationship
Target recognition
Thermodynamics
Urokinase
Urokinase-Type Plasminogen Activator - chemistry
Water chemistry
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Summary: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 > 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 = 40 is adequate to take into account the electrostatic environment at the interface between the proteins, while using a smaller value of (
ISSN:1463-9076
1463-9084
DOI:10.1039/c9cp06530j