Molecular Dynamics Reveals Complex Compensatory Effects of Ionic Strength on the Severe Acute Respiratory Syndrome Coronavirus 2 Spike/Human Angiotensin-Converting Enzyme 2 Interaction

Abstract

The SARS-CoV-2 pandemic has already killed more than one million people worldwide. To gain entry, the virus uses its Spike protein to bind to host hACE-2 receptors on the host cell surface and mediate fusion between viral and cell membranes. As initial steps leading to virus entry involve significant changes in protein conformation as well as in the electrostatic environment in the vicinity of the Spike/hACE-2 complex, we explored the sensitivity of the interaction to changes in ionic strength through computational simulations and surface plasmon resonance. We identified two regions in the receptor-binding domain (RBD), E1 and E2, which interact differently with hACE-2. At high salt concentration, E2-mediated interactions are weakened but are compensated by strengthening E1-mediated hydrophobic interactions. These results provide a detailed molecular understanding of Spike RBD/hACE-2 complex formation and stability under a wide range of ionic strengths.

Molecular dynamics analysis of fast-spreading severe acute respiratory syndrome coronavirus 2 variants and their effects in the interaction with human angiotensin-converting enzyme 2

“…Molecular dynamics (MD) simulations analysis showed that hACE2 presented different backbone root-mean-square deviation (RMSD) and backbone root-meansquare fluctuation (RMSF) profiles in the presence of different RBD variants, RBD B.1.1.7 , RBD B.1.351 and, RBD P.1 (RBD variants ) (Figures 2 and S2). Consistent with our previous study 16 2a). While interacting with RBD B.1.351 , hACE2 visits one major state (Figure 2a).…”

“…In order to evaluate the potential impact of fast-spreading variants B.1.1.7 (RBD B.1.1.7 ), B.1.351 (RBD B.1.351 ), and P.1 (RBD P.1 ) in the interaction with hACE2, we performed molecular dynamics (MD) simulations for 100 ns using RBD (residues 333-526) and hACE2 (residues 19-615) (Figure 2). SARS-CoV-2 RDB binds to hACE2 through two different regions, the E1 (residues 417, 455-456, and 470-490) and E2 (444-454 and 493-505) (Figure 1b) 16 . While E1 mediates more hydrophobic interactions, E2 mediates mostly polar interactions with hACE2.…”

SARS-CoV-2 virion physicochemical characteristics pertinent to abiotic substrate attachment

“…The influence of ionic strength varied by NaCl between 0.15 and 1 M on the free energy of SARS-CoV-2 RBD binding to the ACE2 receptor was studied in Ref. [ 40 ] by molecular dynamics modeling and experimentally by the Surface Plasmon Resonance (SPR) measurements. Using the free energy, it is predicted that the dissociation constant is equal to 7×10 -10 , 2.9×10 -8 and 1×10 -9 M for NaCl concentration equal to 0.15, 0.5 and 1 M, respectively.…”

In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor

“…[ 26 ] reported a structure-based drug design (SBDD) case study using docking and MD simulation to find potential therapeutic targets for wild type of SARS-CoV-2 RBD; Silva de Souza et al . [ 27 ] employed MD simulation to help understand the ionic effects on wild RBD/hACE2 complex formation/stability and reported two regions on wild RBD, which can interact with hACE2 differently; de Andrade et al . [ 28 ] reported the binding affinities of wild SARS-CoV spike protein and wild SARS-CoV-2 spike protein with hACE2 and provided detailed analysis to help gain a clearer view on the binding process between two viruses.…”