Structure, interface stability and hot-spots identification for RBD(SARS-CoV-2):hACE2 complex formation

ABSTRACT

The nature of intermolecular interactions between the SARS-CoV-2 receptor binding domain (RBD) and its receptor, human angiotensin-converting enzyme 2 (hACE2) has been investigated by Langevin simulations to provides clarity from a dynamic and energetic point of view. Hinge prediction and cross-correlation matrix analysis by elastic network models were applied to better understand the interface dynamics that promote the interdomain surface complementarity adjustment. Main results regarding dynamic aspects indicate that there is a large network of different types of interactions i.e. hydrogen bonding, salt bridges and numerous hydrophobic interactions stabilising the complex. With respect to the energetic aspects, we identified and evaluated the energy strength of the primary amino acids involved in the interaction that likely stabilise complex formation. Our results indicate that Tyr449, Leu455, Phe456, Ala475, Phe486, Gln493, Gly496, Gln498, Thr500, Asn501, Gly502, and Tyr505 form the primary interface between the SARS-CoV-2 RBD and hACE2.

KEYWORDS:

• hACE2
• spike
• coronavirus
• COVID-19
• pandemic

Acknowledgments

This research was also supported by PIP 090CO CONICET. H.A.B. gratefully acknowledges Dr. David A. Case (Dept. of Chemistry & Chemical Biology, Rutgers University, USA) for providing him access to the Amber20 suite of programs, and Dr. John Z.H. Zhang (Centre for Computational Chemistry at NYU Shanghai, China) for help us to perform the interaction entropy calculations. We would also like to thank Dra. M. Silvia Di Genaro (IMIBIO-SL, CONICET, UNSL) and Dr. Eduardo A. Callegari (Proteomics Core Facility, Sanford School of Medicine, University of South Dakota, USA) for many stimulating discussions.

Disclosure statement

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

Notes

Only events with occupancy time >10% of the simulation time are shown.

^a Hydrogen-Acceptor distance cutoff dH … A ≤ 3.0 Å and the Donor-H-Acceptor angle cutoff αDHA ≥ 135.0°.

^b Donor-Acceptor distance cutoff dDA ≤ 3.0 Å and the Donor-Acceptor angle cutoff αDA ≥ 135.0°.

^c Distance cutoff d ≤ 8.0 Å and no angle cutoff.

^d Gln498 aceptor residue and Gln42 as donor residue.

^e Gln42 aceptor residue and Gln498 as donor residue.

^a Average contributions to the binding free energies in the RBD:hACE2 complex calculated over the final 40 ns of each replica. Errors, given in parentheses, correspond to mean standard deviations.

Additional information

Funding

Grants from Universidad Nacional de San Luis (UNSL-Argentina) and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET-Argentina) PIP 090CO, partially supported this work.