Modified heated CGMD simulations for discovering stable docked conformations of BiTE antibody against CD3 and CD117/c-kit

ABSTRACT

In cancer immunotherapy, the design and optimisation of bispecific antibodies hold great promise. Bispecific T-cell engager (BiTE) antibodies targeting CD3 and CD117/c-kit have shown significant potential in experimental settings. Nevertheless, knowledge on their stable docked conformations at molecular level is still limited. This study presents an approach of employing modified heated coarse-grained molecular dynamics (CGMD) simulations to elucidate the stable docked conformations of BiTE antibodies against CD3 and CD117/c-kit. We integrated molecular dynamics simulation with coarse-grained and temperature control to explore the conformational landscape of these complex interactions. The modified heated CGMD simulation aimed to re-assess the docked poses suggested by ClusPro webserver. Furthermore, the all-atomic trajectories unveiled the dynamic residues formed throughout the simulation process. The per-residue-energy-binding emphasised the crucial amino acids involved in binding within the complex especially between the complementarity-determining regions (CDR) of BiTEs and residues located at the N-terminal of CD117/c-kit and the C-terminal of CD3. The formation of three types of interactions, such as hydrogen bonds, salt-bridge contact and hydrophobic interactions plays a crucial role in the motion, configuration and the free energy landscape of the complexes. This method is a valuable tool for rational drug design especially in the field of cancer immunotherapy.

KEYWORDS:

• CD3
• CD117/c-kit
• bispecific T-cell engager antibody
• modified heated CGMD simulations
• binding free energy

Acknowledgements

The authors extend their appreciation to the School of Distance Education for furnishing the computational resources. Authors’ contribution: MTCO contributed to the conceptualisation and study design, conducted computational experiments, analysed the trajectories, prepared the figures and tables and wrote the draft for the main manuscript. MACN conducted computational experiments, analysed the trajectories, prepared the figures and reviewed and edited the manuscript. FFNAK conducted computational experiments, prepared the figures and reviewed and edited the manuscript. ANS developed and supplied the automated bash file for all-atomic reverse transformation and reviewed and edited the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Ministry of Higher Education Malaysia (MOHE) under Fundamental Research Grant Scheme (FRGS) grant number FRGS/1/2020/STG02/USM/03/2.