Document text
Principal Investigator: Jin Liu
Organization: WASHINGTON STATE UNIVERSITY
Fiscal Year: 2023
Award: $278,687
Funding agency: National Institute of General Medical Sciences
Virus infections remain major threats to human health worldwide as demonstrated by COVID-19
pandemic caused by SARS-CoV-2 and its variants. All enveloped viruses must fuse with host membranes
to initiate the infection process. Membrane fusion is a critical, but poorly understood biological process
that is driven by protein conformational changes. Membrane fusion is a highly complex, multistage and
multiscale process, which is difficult to investigate through scale-specific techniques (both experimentally
and numerically). In this project, we propose to investigate the structural changes of fusion proteins and
virus fusion through a combination of multiscale modeling, machine learning, and complementary
experimentation. Because of our decades long experience in working with the herpes simplex virus
(HSV), we will utilize the herpesvirus fusogen, gB, a class Ill fusion protein, as a model protein, to
elucidate protein conformational changes during virus fusion. The specific research aims are: (1) To
delineate the conformational changes of viral fusion proteins, through development of the machine
learning facilitated enhanced sampling scheme for fusion proteins and delineation of the sequential
conformation changes of gB protein for HSV fusion by a combination of machine learning and
experiments; (2) To elucidate membrane fusion driven by viral fusion protein conformational changes,
through development of a multiscale model for membrane fusion, assessment of the role of membrane
fluidity in fusion and elucidation of the importance of the gB membrane proximal region on gB
conformational changes and membrane fusion through combined simulations and experiments.
This research will establish experimentally validated, powerful modeling platforms for exploration of the
protein conformational changes and will bridge the multiple spatial and temporal scales involved in the
fusion process. The machine learning method for enhanced sampling is highly innovative and crucial to
capture the large-scale structural (conformational) changes and associated energy profiles of fusion
proteins, and to identify the appropriate pathways during the fusion process. The integration of the
gradient-based optimization method to the machine learning algorithm is novel to identify the most
appropriate reaction coordinates.
Terms: <1918 H1N1><1918 influenza A virus><1918 influenza H1N1 virus><1918 influenza virus><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS Virus><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Bilayer Fluidity><Biological><Biological Function><Biological Process><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 virus><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 virus><Cell Body><Cell membrane><Cells><Chimera Protein><Chimeric Proteins><Cholesterol><Clinical Treatment Moab><CoV emergence><CoV-2><CoV2><Complex><Computer Models><Computer Simulation><Computer based Simulation><Computerized Models><Cytoplasmic Membrane><Dengue><Development><Dimensions><Endocytosis><Envelope Protein><Event><Exocytosis><Fertilized Egg><Fertilized Ovum><Freedom><Fusion Protein><Future><Grain><HIV><HSV><Health><Herpes Simplex Virus><Herpes labialis Virus><Herpesviridae><Herpesviruses><Human><Human Immunodeficiency Viruses><Infection><LAV-HTLV-III><Liberty><Lipids><Liquid substance><Lymphadenopathy-Associated Virus><Machine Learning><Measurement><Membrane><Membrane Fluidity><Membrane Fusion><Methods><Modeling><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Molecular Stereochemistry><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><NIGMS><National Institute of General Medical Sciences><Organism><Pathway interactions><Plasma Membrane><Process><Protein Conformation><Proteins><Reaction><Research><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Scheme><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Simplexvirus><Solid><Spanish flu><Spanish influenza><Sperm><Spermatozoa><Structure><Surface><Techniques><Variant><Variation><Viral><Viral Diseases><Viral Fusion Proteins><Virion><Virus><Virus Diseases><Virus Particle><Virus-HIV><Wuhan coronavirus><biologic><computational modeling><computational models><computational simulation><computer based models><computerized modeling><computerized simulation><conformation><conformational><conformational state><conformationally><conformations><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus emergence><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus emergence><developmental><effective intervention><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><env Antigens><env Gene Products><env Polyproteins><env Protein><experience><experiment><experimental research><experimental study><experiments><flexibility><flexible><fluid><hCoV19><herpes virus><innovate><innovation><innovative><insight><liquid><living system><mAbs><machine based learning><machine learned algorithm><machine learning algorithm><machine learning based algorithm><machine learning based method><machine learning method><machine learning methodologies><membrane model><membrane structure><molecular modeling><monoclonal Abs><mortality><multi-scale computational modeling><multi-scale mathematical modeling><multi-scale modeling><multidisciplinary><multiscale computational modeling><multiscale mathematical modeling><multiscale modeling><mutant><nCoV><nCoV2><nano sized><nanosized><neural network><new CoV><new corona virus><new coronavirus><novel><novel CoV><novel corona virus><novel coronavirus><obligate intracellular parasite><pathogen><pathway><plasmalemma><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><simulation><social role><sperm cell><viral infection><virus infection><virus-induced disease><zoosperm><zygote>