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Evaluating the Efficiency of the Martini Force Field to Study Protein Dimerization in Aqueous and Membrane Environments

preprint
submitted on 25.04.2021, 00:18 and posted on 26.04.2021, 14:32 by Christos Lamprakis, Ioannis Andreadelis, John Manchester, Camilo Velez-Vega, José S. Duca, Zoe Cournia

Protein-protein complex assembly is one of the major drivers of biological response. Understanding the mechanisms of protein oligomerization/dimerization would allow one to elucidate how these complexes participate in biological activities and could ultimately lead to new approaches in designing novel therapeutic agents. However, determining the exact association pathways and structures of such complexes remains a challenge. Here, we use parallel tempering metadynamics simulations in the well-tempered ensemble to evaluate the performance of Martini 2.2P and Martini open-beta 3 (Martini 3) force fields in reproducing the structure and energetics of the dimerization process of membrane proteins and proteins in an aqueous solution in reasonable accuracy and throughput. We find that Martini 2.2P systematically overestimates the free energy of association by estimating large barriers in distinct areas, which likely leads to overaggregation when multiple monomers are present. In comparison, the less viscous Martini 3 results in a systematic underestimation of the free energy of association for proteins in solution, while it performs well in describing the association of membrane proteins. In all cases the near-native dimer complexes are identified as minima in the free energy surface albeit not always as the lowest minima. In the case of Martini 3 we find that the spurious supramolecular protein aggregation present in Martini 2.2P multimer simulations is alleviated and thus this force field may be more suitable for the study of protein oligomerization. We propose that the use of enhanced sampling simulations with a refined coarse-grained force field and appropriately defined collective variables is a robust approach for studying the protein dimerization process, although one should be cautious of the ranking of energy minima.

Funding

This work was supported by computational time granted from the Greek Research & Technology Network (GRNET) in the National HPC facility—ARIS—under Project IDs pr007019/kras. Τhe research project was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “1st Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 1780), awarded to ZC. The authors acknowledge the use of Fenix Infrastructure resources, which are partially funded from the European Union's Horizon 2020 Research and Innovation programme through the ICEI project under grant agreement No. 800858.

History

Email Address of Submitting Author

zcournia@bioacademy.gr

Institution

Biomedical Research Foundation of the Academy of Athens

Country

Greece

ORCID For Submitting Author

0000-0001-9287-364X

Declaration of Conflict of Interest

None

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