SARS-CoV-2 Fusion Peptide has a Greater Membrane Perturbating Effect than SARS-CoV with Highly Specific Dependence on Ca2+

Coronaviruses are a major infectious disease threat, and include the zoonotic-origin human pathogens SARS-CoV-2, SARS-CoV, and MERS-CoV (SARS-2, SARS-1, and MERS). Entry of coronaviruses into host cells is mediated by the spike (S) protein. In our previous ESR studies, the local membrane ordering effect of the fusion peptide (FP) of various viral glycoproteins including the S of SARS-1 and MERS has been consistently observed. We previously determined that the sequence immediately downstream from the S2’ cleavage site is the bona fide SARS-1 FP. In this study, we used sequence alignment to identify the SARS-2 FP, and studied its membrane ordering effect. Although there are only three residue difference, SARS-2 FP induces even greater membrane ordering than SARS-1 FP, possibly due to its greater hydrophobicity. This may be a reason that SARS-2 is better able to infect host cells. In addition, the membrane binding enthalpy for SARS-2 is greater. Both the membrane ordering of SARS-2 and SARS-1 FPs are dependent on Ca2+, but that of SARS-2 shows a greater response to the presence of Ca2+. Both FPs bind two Ca2+ ions as does SARS-1 FP, but the two Ca2+ binding sites of SARS-2 exhibit greater cooperativity. This Ca2+ dependence by the SARS-2 FP is very ion-specific. These results show that Ca2+ is an important regulator that interacts with the SARS-2 FP and thus plays a significant role in SARS-2 viral entry. This could lead to therapeutic solutions that either target the FP-calcium interaction or block the Ca2+ channel.

An orthotropic electro-viscoelastic model for the heart with stress-assisted diffusion

We propose and analyse the properties of a new class of models for the electromechanics of cardiac tissue. The set of governing equations consists of nonlinear elasticity using a viscoelastic and orthotropic exponential constitutive law, for both active stress and active strain formulations of active mechanics, coupled with a four-variable phenomenological model for human cardiac cell electrophysiology, which produces an accurate description of the action potential. The conductivities in the model of electric propagation are modified according to stress, inducing an additional degree of nonlinearity and anisotropy in the coupling mechanisms, and the activation model assumes a simplified stretch–calcium interaction generating active tension or active strain. The influence of the new terms in the electromechanical model is evaluated through a sensitivity analysis, and we provide numerical validation through a set of computational tests using a novel mixed-primal finite element scheme.