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

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel coronavirus, has brought an unprecedented pandemic to the world and affected over 64 million people. The virus infects human using its spike glycoprotein mediated by a crucial area, receptor-binding domain (RBD), to bind to the human ACE2 (hACE2) receptor. Mutations on RBD have been observed in different countries and classified into nine types: A435S, D364Y, G476S, N354D/D364Y, R408I, V341I, V367F, V483A and W436R. Employing molecular dynamics (MD) simulation, we investigated dynamics and structures of the complexes of the prototype and mutant types of SARS-CoV-2 spike RBDs and hACE2. We then probed binding free energies of the prototype and mutant types of RBD with hACE2 protein by using an end-point molecular mechanics Poisson Boltzmann surface area (MM-PBSA) method. According to the result of MM-PBSA binding free energy calculations, we found that V367F and N354D/D364Y mutant types showed enhanced binding affinities with hACE2 compared to the prototype. Our computational protocols were validated by the successful prediction of relative binding free energies between prototype and three mutants: N354D/D364Y, V367F and W436R. Thus, this study provides a reliable computational protocol to fast assess the existing and emerging RBD mutations. More importantly, the binding hotspots identified by using the molecular mechanics generalized Born surface area (MM-GBSA) free energy decomposition approach can guide the rational design of small molecule drugs or vaccines free of drug resistance, to interfere with or eradicate spike-hACE2 binding.

SARS-CoV-2 Omicron Variant Binds to Human Cells More Strongly than the Wild Type: Evidence from Molecular Dynamics Simulation

“…The same has been mentioned in previous studies. 50 , 51 By combining coarse-grained models 52 with umbrella sampling, reasonable results can be obtained for the absolute value of Δ G bind and K D , 53 but coarse-grained modeling is not sensitive enough to describe effects of mutations.…”

Omicron SARS-CoV-2 Variant Spike Protein Shows an Increased Affinity to the Human ACE2 Receptor: An In Silico Analysis

“…The Alpha variant has a non-synonymous substitution of N501Y, while the Beta variant, as well as Gamma and Mu variants additionally contain the E484K mutation (Table 1). Previous reports showed that these mutations most likely increase the binding affinity of the spike to ACE2 as compared to the WT spike, without affecting its overall structure [13][14][15]. These mutations are located primarily in the protein loops, which due to their high flexibility could likely tolerate the conformational changes associated with the residue substitution.…”

Predicted Epitope Abundance Supports Vaccine-Induced Cytotoxic Protection Against SARS-CoV-2 Variants of Concern

“…Nevertheless, they may be associated with selection by other factors such as transmissibility, as suggested by epidemiological data for the principal strains of concern ( 19 – 21 ). In this context, N354D and V367F increase affinity for the hACE2 receptor, as assessed by molecular dynamics ( 22 ), whereas R346S provides escape from some monoclonal antibodies ( 23 ). The presence of these mutations may therefore add a secondary partial effect that is co-selected by other factors.…”