How does temperature affect the dynamics of SARS-CoV-2 M proteins? Insights from Molecular Dynamics Simulations

Abstract

Enveloped viruses, in general, have several transmembrane proteins and glycoproteins, which assist the virus in entry and attachment onto the host cells. These proteins also play a significant role in determining the shape and size of the newly formed virus particles. The lipid membrane and the embedded proteins affect each other in non-trivial ways during the course of the viral life cycle. Unravelling the nature of the protein-protein and protein-lipid interactions, under various environmental and physiological conditions, could therefore prove to be crucial in development of therapeutics. Here, we study the M protein of SARS-CoV-2 to understand the effect of temperature on the properties of the protein-membrane system. The membrane embedded dimeric M proteins were studied using atomistic and coarse-grained molecular dynamics simulations at temperatures ranging between 10 and 50 ˚C. While temperature induced fluctuations should be monotonic, we observe a steady rise in the protein dynamics up to 40 ˚C, beyond which it surprisingly reverts back to the low temperature behaviour. Detailed investigation reveals disordering of the membrane lipids in the presence of the protein, which induces additional curvature around the transmembrane region. Coarse-grained simulations indicate temperature dependent aggregation of M protein dimers. Our study clearly indicates that the dynamics of membrane lipids and integral M protein of SARS-CoV-2 enables it to better associate and aggregate only at a certain temperature range (i.e., ~30 to 40 ˚C). This can have important implications in the protein aggregation and subsequent viral budding/fission processes.

SARS-CoV-2 Membrane Protein: From Genomic Data to Structural New Insights

“…Systems initial minimization was performed to remove bad contacts using the steepest descent algorithm. In this step, systems were heated with a Berendsen thermostat at 310 K in the canonical ensemble (NVT) over 7 ns, an adequate temperature to use in SARS-CoV-2 M protein MD simulations [ 81 ]. Pressure was kept constant at one bar with an isothermal–isobaric ensemble (NPT) for 20 ns with a semi-isotropic pressure coupling algorithm [ 82 ].…”

Correction to “Elucidation of SARS-Cov-2 Budding Mechanisms through Molecular Dynamics Simulations of M and E Protein Complexes”

“…Indeed, coarsegrained simulations by Rath et al suggest that lower temperatures might be detrimental to M protein dimer interactions, possibly due to an energy barrier from lipid packing around the dimers. 2 In light of these studies and the data from our simulations, we suggest that M protein dimers likely need to interact with each other and possibly with E protein pentamers in order to generate the global curvature needed for budding. As expected given the local curvature in the corrected 4M simulation, the membrane surface areas of the cytosolic and lumenal leaflets stayed roughly equal over the course of the trajectory, though these surface areas fluctuated more than was seen in the 4E simulation (Figure 3B).…”

“…This is consistent with our previous simulation in which the only protein–protein interactions came from a few random contacts between unstructured loops. Since recent studies have suggested that M dimers actually do interact with each other, , we hypothesize that the lack of interactions in our simulation might be due to the simulation’s temperature of 300 K. This temperature is standard for molecular dynamics studies but is lower than human body temperature. Indeed, coarse-grained simulations by Rath et al suggest that lower temperatures might be detrimental to M protein dimer interactions, possibly due to an energy barrier from lipid packing around the dimers .…”

“…Since recent studies have suggested that M dimers actually do interact with each other, , we hypothesize that the lack of interactions in our simulation might be due to the simulation’s temperature of 300 K. This temperature is standard for molecular dynamics studies but is lower than human body temperature. Indeed, coarse-grained simulations by Rath et al suggest that lower temperatures might be detrimental to M protein dimer interactions, possibly due to an energy barrier from lipid packing around the dimers . In light of these studies and the data from our simulations, we suggest that M protein dimers likely need to interact with each other and possibly with E protein pentamers in order to generate the global curvature needed for budding.…”