Comparative Effects of ALA and EPA on the Conformational Stability of Wild-Type and Mutant SARS-CoV-2 Spike-ACE2
Keywords:
alpha-linolenic acid, COVID-19, eicosapentaenoic acid, polyunsaturated fatty acids, spike protein, single nucleotide polymorphismsAbstract
The evolution of SARS-CoV-2 variants through mutations in the Spike (S) protein in the receptor-binding domain (RBD) significantly influences its binding affinity to human Angiotensin-Converting Enzyme 2 (ACE2). While polyunsaturated fatty acids (PUFAs), specifically alpha-linolenic acid (ALA) and eicosapentaenoic acid (EPA), are recognised for their anti-inflammatory properties, their molecular impact on the structural stability and mechanics of the S-ACE2 complex is less understood. This study utilised 100 ns molecular dynamics (MD) simulations to evaluate the modulatory effects of ALA and EPA on both wild-type and mutant S-ACE2 complexes in the presence of the 13 most frequently occurring S mutations in Malaysian patients from August 2023 to January 2024. Analyses of Root Mean Square Deviation (RMSD) and Radius of Gyration (Rg) indicated that the mutant S-ACE2 naturally adopts a more compact yet structurally divergent conformation compared to the wild-type. PUFA binding alters these dynamics; notably, EPA stabilised the mutant S-ACE2 into a conformation resembling the wild-type and markedly decreased per-residue fluctuations (RMSF) in critical interface regions (residues 474–486). Principal Component Analysis (PCA) confirmed that EPA binding restricts the conformational space of both mutant and wild-type S-ACE2. Snapshots at different time points show that the longer carbon chain of EPA binds R408S in mutated S-ACE2, underlying the stable conformation of the complex, whereas ALA, with a shorter carbon chain, does not do so. These findings suggest that ALA and EPA function as structural modulators of the S-ACE2 binding affinities, potentially interfering with the conformational stability required for optimal viral-host interaction. This research provides a molecular basis for the variable impacts of dietary PUFAs to act as structural inhibitors against evolving SARS-CoV-2 variants by disrupting the binding mechanics of the S-protein.
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