Unknown

Dataset Information

0

Bispecific antibodies-effects of point mutations on CH3-CH3 interface stability.


ABSTRACT: A new format of therapeutic proteins is bispecific antibodies, in which two different heavy chains heterodimerize to obtain two different binding sites. Therefore, it is crucial to understand and optimize the third constant domain (CH3-CH3) interface to favor heterodimerization over homodimerization, and to preserve the physicochemical properties, as thermal stability. Here, we use molecular dynamics simulations to investigate the dissociation process of 19 CH3-CH3 crystal structures that differ from each other in few point mutations. We describe the dissociation of the dimeric interface as a two-steps mechanism. As confirmed by a Markov state model, apart from the bound and the dissociated state, we observe an additional intermediate state, which corresponds to an encounter complex. The analysis of the interdomain contacts reveals key residues that stabilize the interface. We expect that our results will improve the understanding of the CH3-CH3 interface interactions and thus advance the developability and design of new antibodies formats.

SUBMITTER: Pomarici ND 

PROVIDER: S-EPMC9741699 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

Bispecific antibodies-effects of point mutations on CH3-CH3 interface stability.

Pomarici Nancy D ND   Fernández-Quintero Monica L ML   Quoika Patrick K PK   Waibl Franz F   Bujotzek Alexander A   Georges Guy G   Liedl Klaus R KR  

Protein engineering, design & selection : PEDS 20220201


A new format of therapeutic proteins is bispecific antibodies, in which two different heavy chains heterodimerize to obtain two different binding sites. Therefore, it is crucial to understand and optimize the third constant domain (CH3-CH3) interface to favor heterodimerization over homodimerization, and to preserve the physicochemical properties, as thermal stability. Here, we use molecular dynamics simulations to investigate the dissociation process of 19 CH3-CH3 crystal structures that differ  ...[more]

Similar Datasets

| S-EPMC11308365 | biostudies-literature
| S-EPMC4403899 | biostudies-literature
| S-EPMC10629431 | biostudies-literature
| S-EPMC9637083 | biostudies-literature
| S-EPMC5012208 | biostudies-literature
| S-EPMC2725416 | biostudies-literature
| S-EPMC5465497 | biostudies-literature
| S-EPMC5606552 | biostudies-literature
| S-EPMC7023245 | biostudies-literature
| S-EPMC3012461 | biostudies-literature