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Registration Number

0225U005360, (0125U001669) , R & D reports

Title

Visualization of intermolecular interactions of coagulation system proteins.

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Вивчення просторової структури комплексу ВbN-домену з аС-регіоном фібрину, що дозволить запропонувати концепцію його участі на етапі побудови протофібрил та під час їхньої латеральної асоціації; створення просторової моделі дезінтегрину з отрути ефи багатолускової, що надасть змогу передбачити особливості його взаємодії з ІІbIIIa-рецептором тромбоцитів; вивчення комплексу тіа-каліксарену з центром полімеризації "А" фібрину, що дозволить передбачити зміни у структурі молекул калікс[4]аренового ряду, які б дозволили збільшити їхню селективність та активність.

Head

Hrabovskyi Oleksii O., Доктор філософії

Registration Date

30-12-2025

Organization

Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine

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To apply in silico methods to establish and build models of intermolecular interactions of proteins involved in the regulation of the hemostatic system. In particular, the formation of the BbN-domain complex with the fibrin аC-region will be investigated, the spatial structure of disintegrin from eсhis multisquamatus venom will be determined, and a thia-calixarene complex with the polymerization center “A” will be proposed.

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The project was dedicated to the investigation of intermolecular interactions among key components of the hemostatic system using modern computational modeling approaches. The main focus was on three key targets: the αC region of fibrinogen, the interaction of the disintegrin from Echis multisquamatus venom with the αIIbβ3 integrin receptor, and the interaction of calix[4]arenes with fibrin. For the αC region of fibrinogen, the spatial structure was predicted using deep learning methods including AlphaFold2, OpenFold, and Chai-1. The quality of the obtained models was evaluated using pLDDT and Predicted Aligned Error (PAE) metrics. It was demonstrated that due to the high conformational flexibility of the αC region, these methods do not provide structurally consistent and reproducible models suitable for subsequent analysis of intermolecular interactions. Therefore, for further studies, a literature-based model of the αC domain, constructed using experimental data and molecular dynamics simulations, was employed and further optimized. The adequacy of the model was validated against proteolytic cleavage sites, as these are generally located in unstructured regions. The disintegrin from Echis multisquamatus venom was identified as a dimeric protein based on mass spectrometry and electrophoretic data. A spatial model of the homodimer was built, and its complex with αIIbβ3 integrin was modeled using crystallographic structures of the integrin in its active conformation. Key residues involved in Mg²⁺ coordination and complex stabilization were identified. Additionally, molecular docking of the thiacalix[4]arene C-201S in its four main conformations was performed at the “A” polymerization center of fibrin. The results allowed for the identification of the macrocycle conformation with the theoretically highest affinity for fibrin, providing a basis for the rational design and modification of calixarenes as potential antithrombotic agents.

Product Description

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Hrabovskyi Oleksii O.

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2025-12-30