Multiscale Modeling of Coronavirus Virions in the Respiratory System

NONTECHNICAL SUMMARY One of the ways COVID-19 spreads is by breathing in small liquid droplets that contain the coronavirus SARS-CoV-2. In order to cause an infection, the virus must first pass from the respiratory tract through a layer of molecular thickness, the lung surfactant film, into the lung. The passage through the lung surfactant film is a process that is not well understood because the coronavirus and lung surfactant film continuously affect and remodel each other. The lung surfactant film is a complex and fragile nanoscale biomaterial that consists mostly of surfactant molecules. Certain types of surfactant molecules are capable of destabilizing and breaking up the coronavirus. This capability may be utilized by the medical administration of exogenous surfactants in surfactant therapy, which is currently being tested in clinical trials as a COVID-19 treatment approach. This award supports computational research and educational activities to study in detail and on a molecular level how SARS-CoV-2 and its variants adhere to the lung surfactant film, how the virus particle is capable of passing through the film, and how surfactant molecules affect this process. The computational research method, known as molecular dynamics, is applied with the goal to learn how pathophysiological behavior can emerge from the material properties of lung surfactant layer and associated coronavirus particles. The materials-centric approach places this research at the interface between condensed matter physics and biology. Among the broader impacts is the potential to inform the search for novel therapeutic pathways that inhibit coronavirus activity by using exogenous surfactants. Educational and mentoring aspects of this project include training graduate and undergraduate students from diverse backgrounds and developing teaching modules on the modeling of complex biological nanoscale systems. The developed simulation codes will be made available for the scientific community through curated data repositories. TECHNICAL SUMMARY COVID-19 is transmitted by inhaling airborne coronavirus particles, SARS-CoV-2, which penetrate the respiratory system and cause severe acute respiratory syndrome (SARS) that can lead to lung failure. SARS-CoV-2 virions are spheroidal nanoparticles, with a lipid bilayer envelope of about 85 nanometer diameter decorated by a “crown” of 20 nanometer long spike protein protrusions. Whereas our knowledge of the biochemical structure and functions of SARS-CoV-2 is quickly growing, the interfacial properties of the virions, as nanoparticles interacting with the respiratory system environment, have not been addressed and are poorly understood. Bridging this knowledge gap is important for informing clinical studies on surfactant therapies to treat SARS by administering exogenous surfactants. This project aims at using multiscale molecular dynamics simulations to explore the fundamental mechanisms of interactions of SARS-CoV-2 virions with lung surfactant films and their fate in the respiratory system. Consideration of SARS-CoV-2 virions and the lung surfactant film as nanoscale multifunctional biomaterials that interact within the respiratory system environment represents the main methodological novelty of the project. The PI will (a) develop original coarse-grained computational models of SARS-CoV-2 virions and lung surfactant films, (b) establish in-silico the molecular mechanisms of the SARS-CoV-2 virion interfacial interactions with lung surfactant films and exogenous biosurfactants, and (c) explore the effects of these interactions on the stability of lung surfactant films and the fate of SARS-CoV-2 virions in the respiratory system. The project will produce multiscale computational models of interfacial processes involving SARS-CoV-2 variants to address the currently unresolved questions: (1) how sorption of lung surfactant lipids and proteins affects the envelope membrane and spike proteins, (2) how SARS-CoV-2 virions affect the integrity and stability of lung surfactant films, (3) if detergent activity and sorption of pulmonary and exogenous surfactants can induce lysis of the viral envelope, and (4) to what extent the difference in specifics of lung surfactant interactions with mutated SARS-CoV-2 virions may explain why some coronavirus variants cause more infections and spread faster than others. Special attention will be paid to the differences between SARS-CoV-2 variants with respect to adhesion of pulmonary and exogenous surfactants. Answers to these questions will advance fundamental understanding of SARS-CoV-2 virions and lung surfactant films as interacting nanoscale biomaterials and may have clinical implications for the selection of exogenous surfactants for prophylaxis and treatment of COVID-19. The PI expects the project will have an interdisciplinary transformative impact by advancing computational studies of pathophysiological behavior and fate of coronavirus virions in pulmonary environment, surfactant-induced inhibition of the viral activity, as well as adhesion and translocation of synthetic virion-type drug carrier nanoparticles through cell membranes and other physiological interfaces. The proposed research will support diversity, train graduate and undergraduate students, and produce modules on the modeling of complex biological nanoscale systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.