Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

Abstract

COVID-19 is characterized by an unprecedented abrupt increase in the viral transmission rate (SARS-CoV-2) relative to its pandemic evolutionary ancestor, SARS-CoV (2003). The complex molecular cascade of events related to the viral pathogenicity is triggered by the Spike protein upon interacting with the ACE2 receptor on human lung cells through its receptor binding domain (RBD Spike ). One potential therapeutic strategy to combat COVID-19 could thus be limiting the infection by blocking this key interaction. In this current study, we adopt a protein design approach to predict and propose non-virulent structural mimics of the RBD Spike which can potentially serve as its competitive inhibitors in binding to ACE2. The RBD Spike is an independently foldable protein domain, resilient to conformational changes upon mutations and therefore an attractive target for strategic re-design. Interestingly, in spite of displaying an optimal shape fit between their interacting surfaces (attributed to a consequently high mutual affinity), the RBD Spike –ACE2 interaction appears to have a quasi-stable character due to a poor electrostatic match at their interface. Structural analyses of homologous protein complexes reveal that the ACE2 binding site of RBD Spike has an unusually high degree of solvent-exposed hydrophobic residues, attributed to key evolutionary changes, making it inherently “reaction-prone.” The designed mimics aimed to block the viral entry by occupying the available binding sites on ACE2, are tested to have signatures of stable high-affinity binding with ACE2 (cross-validated by appropriate free energy estimates), overriding the native quasi-stable feature. The results show the apt of directly adapting natural examples in rational protein design, wherein, homology-based threading coupled with strategic “hydrophobic ↔ polar” mutations serve as a potential breakthrough. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00894-021-04779-0.

Capturing a crucial ‘disorder-to-order transition’ at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges

“…Alarming concerns have thus been unavoidable ever since on the ethical grounds of the decades-long practices of 'gain of function' research in virology [12][13][14]. Apart from the presence of the FLCS in the SARS-CoV-2 Spike (FLCS Spike : absent in other beta-CoVs) the other most striking evolutionary feature of SARS-CoV-2 has been its RBD Spike [15] which is highly optimized for binding with its human host receptor, hACE2 (among all species known to harbor homologous receptors [16,17]), thus channeling the viral influx heavily towards the human population. Both these features, collectively and on their own, present a certain degree of abruptness considering both the time-scale and the sequential nature of changes attributed to natural evolution.…”

“…This "down-to-up" transition of RBD Spike enables it to dock to the solvent exposed hACE2 molecular surface. The RBD Spike -hACE2 interaction, reminiscent of a molecular handshake [15], serves as a molecular switch in the viral cell entry. The RBD Spike -hACE2 interface has a low electrostatic matching [15], characteristic of quasistable interactions and therefore perhaps best-fitted for (transient) molecular switches.…”

BRANEart: Identify Stability Strength and Weakness Regions in Membrane Proteins

“…BRANEart has recently been applied in the context of COVID-19 research to cross-check the correctness of docked peptide-protein complexes between angiotensin II and its cognate receptor, angiotensin converting enzyme 2 (ACE2)(Basu et al, 2021).…”

Special Issue on ‘Coronavirus: Vaccines and Other Therapeutics’ (2020–2021)

“…The efforts have already resulted in the development of several approved vaccines [5][6][7] which are being recommended and administered at a mass-scale by governments in and across countries and continents. In parallel, several plausible alternative therapeutics have also been proposed, mostly based on rationalized computational predictions [8][9][10], some of which have even passed their wet-lab validation tests and early rounds of clinical trials [11] in global academia. The re-purposing of known drugs [12,13] and/or earlier vaccines have also been attempted and so has been antisera from convalescent patients in order to procure templates of efficient antibodies for further modulation and structural optimization [14,15].…”

“…Even with this handicap, a wide variety of main-stream therapeutics (referring primarily to the approved vaccines) have been procured, recommended and administered globally, resulting in 30.5% of the global human population of 7.9 billion being fully vaccinated while 42.8% being partly (dated 15 September 2021 [23]). Alongside with these mainstream approaches, alternative therapeutic directions (including 'reverse' approaches [9]) have also being explored (Table 1), presenting a whole spectrum from the design of mini-proteins [8], peptide blockers [24], nanobodies [10], RBD Spike structural mimics [9], influenza virus-like particle (VLP) vaccines [25] and possibly others. Studies on natural products [26][27][28] promised to serve as possible 'herbal medicines' for the future have also been reported in great number.…”