Molecular Dynamics Simulations of Viral Spike Proteins
Authors:   , Gupta Natasha , Abrams Cameron F. 
Published: November 2022

Two of the most significant pandemics we have experienced in the past century are the AIDS pandemic caused by HIV-1, which has been ongoing since the 1980s, and COVID-19, caused by SARS-CoV-2, which was declared a pandemic in 2020. The impact of these viruses is global and ongoing. SARS-CoV-2 is a novel coronavirus that was first identified in Wuhan, China, in December 2019. The virus was found to cause a respiratory illness that was later named COVID-19. The disease spread rapidly throughout the world, and in March 2020, the World Health Organization declared it a pandemic. SARS-CoV-2 functions by infecting host cells in the throat and lungs via the ACE2 receptor on the host cells. There is no cure, but several vaccines and antiviral therapies have received emergency use authorization and now have full authorization from the FDA. More than 400 million cases and more than 6 million deaths have occurred since the onset of Covid-19 in 2020. AIDS has led to greater than 36 million deaths in total since the 1980s and almost 700 thousand deaths in just 2020. HIV-1, the virus that causes AIDS, functions by infecting CD4+ lymphocytes, and there is no cure or vaccine, but there are 26 FDA-approved antiretroviral therapy (ART) drugs currently on the market. Although treatment has curbed the deaths worldwide of these diseases, we have not entirely eradicated these diseases. Therefore, there is a need for more effective therapeutics to help minimize this death toll, and studying these viruses is essential to getting us closer to that position. SARS-CoV-2 and HIV-1 are enveloped viruses that depend on a class I viral fusion protein for infection and subsequent replication. Both viruses' genomes encode a trimeric glycoprotein that mediates host cell entry. In HIV-1, this is the envelope (Env) spike glycoprotein, and in SARS-CoV-2, it is the spike (S) glycoprotein. This work seeks to elucidate the structure-function relationships of these spike proteins using molecular dynamics simulations. The goal is also to identify residues of interest that may lead to developing more potent therapeutics that span a wider range of variants by inhibiting viral entry before infection occurs. This thesis is composed of eleven chapters divided into four parts. Part one of this work provides background, motivation, and methodologies used in the following sections. An overview of viral fusion proteins is presented. Then the background of each virus, HIV-1 and SARS-CoV-2, is provided, including its entry mechanisms, structure, and available therapeutics. Finally, we detail the methodologies used in this work to probe each virus. Part two of this work focuses on molecular simulations of HIV-1 Env. First, specific methodologies are presented to estimate the binding free energy of known small-molecule inhibitors across HIV-1 variants. Observations are made that relate specific residue mutations to small molecule activity. Thereafter, a workflow for developing predictive activity from the SMILES structure of small molecules is proposed. The third part of this work focuses on molecular simulations of SARS-CoV-2 S. The energetics of a necessary pre-recognition conformational change are presented. Observations on the energetics of the Delta variant are also discussed. Next, the effect of specific mutations on the binding of the receptor binding domain, RBD, a subunit of SARS-CoV-2 S to ACE2, is presented. This part of the dissertation concludes by discussing the effect of temperature on SARS-CoV-2 S. The fourth part of this work reviews the conclusions, accomplishments, and impact of the presented work. This dissertation concludes by discussing the outlook and future work that could be derived as a result.