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Principal Investigator: JEAN S BAUM
Organization: RUTGERS, THE STATE UNIV OF N.J.
Fiscal Year: 2021
Award: $221,154
Funding agency: National Institute of General Medical Sciences
Abstract
The overarching goal in this proposal is to understand how molecular motions and biophysical properties
modulate protein interactions to promote normal homeostasis or pathological disease states. We investigate
the relationship between protein dynamics and interactions in three contexts: 1) protein–fibrillar collagen
interactions involved in platelet aggregation; 2) α-synuclein (αS), an intrinsically disordered protein (IDP)
whose misfolding and aggregation into amyloid fibrils and deposition into Lewy bodies are associated with
debilitating synucleinopathies, such as Parkinson's Disease; and 3) the spike glycoprotein of the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), whose interaction with angiotensin converting enzyme 2
(ACE2) via the receptor binding domain (RBD) is the initial point of host cell entry. We have recently
discovered that in each of these cases, conformational dynamics profoundly impact their atomic-to-nano scale
properties and may affect their potential for biomolecular interactions. Despite the biological importance of
these systems and the implications for their interactions on disease, the molecular determinants of these
protein–protein interactions remain unanswered. Thus, we use a multifaceted approach integrating solution
and solid-state NMR with biophysical, biological, and computational methods to address how molecular
motions modulate protein interactions to promote normal homeostasis or pathological disease states. Gaining
a molecular understanding of protein–protein interactions with each of these dynamic systems relies on state-
of-the-art solution NMR instrumentation to be able to accurately measure timescales and fluctuations of these
interaction events and to detect transient, lowly populated complexes.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><Address><Affect><Amyloid Fibrils><Amyloid deposition><Autoregulation><Biological><Biophysics><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Assay><Cellular Function><Cellular Physiology><Cellular Process><CoV-2><CoV2><Collagen Fibril><Complex><Computing Methodologies><Disease><Disorder><Event><Fibrillar Collagen><Goals><Health><Homeostasis><Intervention><Intervention Strategies><Lewy Bodies><Measures><Mediating><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Motion><NAC precursor><PARK1 protein><PARK4 protein><Paralysis Agitans><Parkinson><Parkinson Disease><Parkinson's disease><Parkinsons disease><Pathologic><Physiological Homeostasis><Platelet aggregation><Primary Parkinsonism><Property><Protein Dynamics><Proteins><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SNCA><SNCA protein><SSNMR><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-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Subcellular Process><System><Therapeutic><Wuhan coronavirus><a-syn><a-synuclein><alpha synuclein><alphaSP22><angiotensin converting enzyme 2><angiotensin converting enzyme II><biophysical characteristics><biophysical characterization><biophysical equipment><biophysical foundation><biophysical measurement><biophysical parameters><biophysical principles><biophysical properties><biophysical sciences><biophysical tools><cell assay><computational methodology><computational methods><computer based method><computer methods><computing method><conformation><conformational state><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><design><designing><dynamic system><dynamical system><hCoV19><instrumentation><interventional strategy><monomer><nCoV2><nano meter scale><nano meter sized><nano scale><nanometer scale><nanometer sized><nanoscale><non A-beta component of AD amyloid><non A4 component of amyloid precursor><protein protein interaction><receptor binding><receptor bound><self assembly><solid state NMR><solid state nuclear magnetic resonance><synucleinopathy><α-syn><α-synuclein>