Abstract
The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has no publicly available vaccine or antiviral drugs at the time of writing. An attractive coronavirus drug target is the main protease (Mpro, also known as 3CLpro) because of its vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which bind and block the active site of the main protease, but little has been done to address potential non-competitive inhibition, targeting regions other than the active site, partly because the fundamental biophysics of such allosteric control is still poorly understood. In this work, we construct an elastic network model (ENM) of the SARS-CoV-2 Mpro homodimer protein and analyse its dynamics and thermodynamics. We found a rich and heterogeneous dynamical structure, including allosterically correlated motions between the homodimeric protease's active sites. Exhaustive 1-point and 2-point mutation scans of the ENM and their effect on fluctuation free energies confirm previously experimentally identified bioactive residues, but also suggest several new candidate regions that are distant from the active site, yet control the protease function. Our results suggest new dynamically driven control regions as possible candidates for non-competitive inhibiting binding sites in the protease, which may assist the development of current fragment-based binding screens. The results also provide new insights into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure.
Highlights
Over 2020, a rapidly spreading disease named COVID-19 caused by the novel coronavirus SARS-CoV-2 has generated a global pandemic
We present structural and functional detail of the SARS-CoV-2 main protease (Mpro) as further essential background, describe our simulations and their results, before concluding with a discussion of the potential to exploit its dynamical allostery for non-competitive inhibition
In another study, researchers found the root mean square deviation (RMSD) of 0.53 Å for apo forms of two corona viruses’ main proteases (PDB accession 2bx4 and 6y2e) [13]. These findings together evidence that the N214A mutation operates through a fluctuation allostery mechanism and structural similarities between two proteases motivate the analysis of the coarsegrained dynamic structure of SARS-CoV-2 Mpro reported here
Summary
Over 2020, a rapidly spreading disease named COVID-19 caused by the novel coronavirus SARS-CoV-2 has generated a global pandemic. This study, and others, have shown that, while the huge reduction in the number of degrees of freedom that the ENM constitutes does not capture the quantitative values of free energies, or the numerical changes to those values on mutation that are seen in experiment, it can rank them qualitatively, and identify the functional form of the thermal dynamics of a protein for a significant set of low-frequency modes Those aspects of protein function that rely on side-chain structures and interactions, or on very fast processes, are not captured by any coarse-grained model, including those of the ENM class. We present structural and functional detail of the SARS-CoV-2 Mpro as further essential background, describe our simulations and their results, before concluding with a discussion of the potential to exploit its dynamical allostery for non-competitive inhibition
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