Multiscale MD simulations of wild-type and sickle hemoglobin aggregation.

Autor: Olagunju MO; Institute of Biological Information Processing, Structural Biochemistry, Forschungszentrum Jülich, Jülich, Germany., Loschwitz J; Institute of Biological Information Processing, Structural Biochemistry, Forschungszentrum Jülich, Jülich, Germany.; Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Olubiyi OO; Institute of Biological Information Processing, Structural Biochemistry, Forschungszentrum Jülich, Jülich, Germany.; Department of Pharmaceutical and Medicinal Chemistry, College of Pharmacy, Afe Babalola University, Ado-Ekiti, Nigeria.; Institute of Drug Research and Development, Bogoro Centre, Afe Babalola University, Ado-Ekiti, Nigeria., Strodel B; Institute of Biological Information Processing, Structural Biochemistry, Forschungszentrum Jülich, Jülich, Germany.; Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Jazyk: angličtina
Zdroj: Proteins [Proteins] 2022 Nov; Vol. 90 (11), pp. 1811-1824. Date of Electronic Publication: 2022 May 18.
DOI: 10.1002/prot.26352
Abstrakt: Sickle cell disease is a hemoglobinopathy resulting from a point mutation from glutamate to valine at position six of the β-globin chains of hemoglobin. This mutation gives rise to pathological aggregation of the sickle hemoglobin and, as a result, impaired oxygen binding, misshapen and short-lived erythrocytes, and anemia. We aim to understand the structural effects caused by the single Glu6Val mutation leading to protein aggregation. To this end, we perform multiscale molecular dynamics simulations employing atomistic and coarse-grained models of both wild-type and sickle hemoglobin. We analyze the dynamics of hemoglobin monomers and dimers, study the aggregation of wild-type and sickle hemoglobin into decamers, and analyze the protein-protein interactions in the resulting aggregates. We find that the aggregation of sickle hemoglobin is driven by both hydrophobic and electrostatic protein-protein interactions involving the mutation site and surrounding residues, leading to an extended interaction area and thus stable aggregates. The wild-type protein can also self-assemble, which, however, results from isolated interprotein salt bridges that do not yield stable aggregates. This knowledge can be exploited for the development of sickle hemoglobin-aggregation inhibitors.
(© 2022 The Authors. Proteins: Structure, Function, and Bioinformatics published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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