Evaluation of the impact of two C5 genetic variants on C5-eculizumab complex stability at the molecular level

Abstract

Complement C5 is the target of the monoclonal antibody eculizumab, used in complement dysregulating disorders, like the rare disease Paroxysmal Nocturnal Hemoglobinuria (PNH). PNH is an acquired hematopoietic stem cell condition characterized by aberrant destruction of erythrocytes, chronic hemolytic anemia, and thromboembolism propensity. C5 is a protein component of the complement system which is part of the immune system of the body and plays a prominent role in the destruction of red blood cells, misidentifying them as a threat. This work describes the application of molecular dynamics simulations to the study of the underlying interactions between complement C5 and eculizumab. This study also reveals the importance of single nucleotide polymorphisms on C5 protein concerning the effective inhibition of the mAB, involving the mechanistic events taking place at the interface spots of the complex. The predicted conformational change in the C5 Arg⁸⁸⁵/His/Cys mutation has implications on the protein’s interaction with eculizumab, compromising their compatibility. The acquired insights into the conformational changes, dynamics, flexibility, and interactions shed light on the knowledge of the function of this biomolecule providing answers about the poor response to the treatment in PNH patient carriers of the mutations. By investigating the intricate dynamics, significant connections between C5 and eculizumab can be uncovered. Such insights may aid in the creation of novel compounds or lead to the enhancement of eculizumab’s efficacy.

Communicated by Ramaswamy H. Sarma

Keywords:

• Computational simulation
• eculizumab
• complement C5
• genetic polymorphisms
• structural analysis

Authors’ contributions

Data curation, investigation, methodology, VPP and SFS; Formal analysis, VPP and SFS; Resources, SFS; Supervision, SFS and MV; Validation, VPP and SFS; Visualization, VPP and SFS; Writing original draft preparation, VPP and SFS; Writing, review, and editing, VPP, SFS, MV and CP; All authors have read and agreed to the published version of the manuscript.

Availability of data and material

Available upon reasonable request.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This work was financially supported with funding from FCT/MCTES (UIDP/50006/2020) through national funds. Some of the calculations were produced with the support of INCD funded by FCT and FEDER under project 01/SAICT/2016 number 022153 and projects CPCA/A00/7140/2020, CPCA/A00/7145/2020, and 2021.09752.CPCA. SFS acknowledges FCT for funding through program 2020.01423.CEECIND.