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Article ; Online: Free Energy Landscapes from SARS-CoV-2 Spike Glycoprotein Simulations Suggest that RBD Opening Can Be Modulated via Interactions in an Allosteric Pocket.

Fallon, Lucy / Belfon, Kellon A A / Raguette, Lauren / Wang, Yuzhang / Stepanenko, Darya / Cuomo, Abbigayle / Guerra, Jose / Budhan, Stephanie / Varghese, Sarah / Corbo, Christopher P / Rizzo, Robert C / Simmerling, Carlos

Journal of the American Chemical Society

2021 Volume 143, Issue 30, Page(s) 11349–11360

Abstract: The SARS-CoV-2 coronavirus is an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry ... ...

Abstract	The SARS-CoV-2 coronavirus is an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry into the host cell and is the primary target of neutralizing antibodies. The receptor binding domain (RBD) of the spike samples multiple conformations in a compromise between evading immune recognition and searching for the host-cell surface receptor. Using atomistic simulations of the glycosylated wild-type spike in the closed and 1-up RBD conformations, we map the free energy landscape for RBD opening and identify interactions in an allosteric pocket that influence RBD dynamics. The results provide an explanation for experimental observation of increased antibody binding for a clinical variant with a substitution in this pocket. Our results also suggest the possibility of allosteric targeting of the RBD equilibrium to favor open states via binding of small molecules to the hinge pocket. In addition to potential value as experimental probes to quantify RBD conformational heterogeneity, small molecules that modulate the RBD equilibrium could help explore the relationship between RBD opening and S1 shedding.
MeSH term(s)	Allosteric Site ; Molecular Dynamics Simulation ; Protein Domains ; SARS-CoV-2/chemistry ; Spike Glycoprotein, Coronavirus/chemistry ; Thermodynamics
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.1c00556
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Article: Free Energy Landscapes from SARS-CoV-2 Spike Glycoprotein Simulations Suggest that RBD Opening Can Be Modulated via Interactions in an Allosteric Pocket

Fallon, Lucy / Belfon, Kellon A. A. / Raguette, Lauren / Wang, Yuzhang / Stepanenko, Darya / Cuomo, Abbigayle / Guerra, Jose / Budhan, Stephanie / Varghese, Sarah / Corbo, Christopher P. / Rizzo, Robert C. / Simmerling, Carlos

Journal of the American Chemical Society. 2021 July 16, v. 143, no. 30

2021

Abstract	The SARS-CoV-2 coronavirus is an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry into the host cell and is the primary target of neutralizing antibodies. The receptor binding domain (RBD) of the spike samples multiple conformations in a compromise between evading immune recognition and searching for the host-cell surface receptor. Using atomistic simulations of the glycosylated wild-type spike in the closed and 1-up RBD conformations, we map the free energy landscape for RBD opening and identify interactions in an allosteric pocket that influence RBD dynamics. The results provide an explanation for experimental observation of increased antibody binding for a clinical variant with a substitution in this pocket. Our results also suggest the possibility of allosteric targeting of the RBD equilibrium to favor open states via binding of small molecules to the hinge pocket. In addition to potential value as experimental probes to quantify RBD conformational heterogeneity, small molecules that modulate the RBD equilibrium could help explore the relationship between RBD opening and S1 shedding.
Keywords	COVID-19 infection ; Gibbs free energy ; Severe acute respiratory syndrome coronavirus 2 ; glycoproteins ; glycosylation ; viral fusion proteins
Language	English
Dates of publication	2021-0716
Size	p. 11349-11360.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.1c00556
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Article ; Online: The flexibility of ACE2 in the context of SARS-CoV-2 infection

Barros, Emilia P. / Casalino, Lorenzo / Gaieb, Zied / Dommer, Abigail C. / Wang, Yuzhang / Fallon, Lucy / Raguette, Lauren / Belfon, Kellon / Simmerling, Carlos / Amaro, Rommie E.

Biophysical Journal ; ISSN 0006-3495

2020

Keywords	Biophysics ; covid19
Language	English
Publisher	Elsevier BV
Publishing country	us
Document type	Article ; Online
DOI	10.1016/j.bpj.2020.10.036
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The flexibility of ACE2 in the context of SARS-CoV-2 infection.

Barros, Emilia P / Casalino, Lorenzo / Gaieb, Zied / Dommer, Abigail C / Wang, Yuzhang / Fallon, Lucy / Raguette, Lauren / Belfon, Kellon / Simmerling, Carlos / Amaro, Rommie E

Biophysical journal

2020 Volume 120, Issue 6, Page(s) 1072–1084

Abstract: The coronavirus disease 2019 (COVID-19) pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine development efforts are underway, there are many ... ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine development efforts are underway, there are many outstanding questions on the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and host cell entry. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular spike glycoprotein and at the receptor-binding domain (RBD)-receptor interface, suggesting a role in infection. Here, we perform explicitly solvated, all-atom, molecular dynamics simulations of the glycosylated, full-length, membrane-bound ACE2 receptor in both an apo and spike RBD-bound state to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full-length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer and suggests a mechanical contribution of the host receptor toward the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can potentially be exploited for the rational design of effective SARS-CoV-2 therapeutics.
MeSH term(s)	Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/metabolism ; COVID-19/enzymology ; COVID-19/virology ; Humans ; Molecular Dynamics Simulation ; Protein Multimerization ; SARS-CoV-2/physiology
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-11-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2020.10.036
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Article ; Online: Can Macula and Optic Nerve Head Parameters Detect Glaucoma Progression in Eyes with Advanced Circumpapillary Retinal Nerve Fiber Layer Damage?

Lavinsky, Fabio / Wu, Mengfei / Schuman, Joel S / Lucy, Katie A / Liu, Mengling / Song, Youngseok / Fallon, Julia / de Los Angeles Ramos Cadena, Maria / Ishikawa, Hiroshi / Wollstein, Gadi

Ophthalmology

2018 Volume 125, Issue 12, Page(s) 1907–1912

Abstract: Purpose: To evaluate the ability of OCT optic nerve head (ONH) and macular parameters to detect disease progression in eyes with advanced structural glaucomatous damage of the circumpapillary retinal nerve fiber layer (cRNFL).: Design: Longitudinal ... ...

Abstract	Purpose: To evaluate the ability of OCT optic nerve head (ONH) and macular parameters to detect disease progression in eyes with advanced structural glaucomatous damage of the circumpapillary retinal nerve fiber layer (cRNFL). Design: Longitudinal study. Participants: Forty-four eyes from 37 patients with advanced average cRNFL damage (≤60 μm) followed up for an average of 4.0 years. Methods: All patients were examined with spectral-domain OCT and visual field (VF) assessment during at least 4 visits. Main outcome measurements: Visual field mean deviation (MD) and VF index. OCT cRNFL (average, superior, and inferior quadrants), ganglion cell-inner plexiform layer (GCIPL) (average, superior, and inferior), rim area, cup volume, average cup-to-disc (C:D) ratio, and vertical C:D ratio. Results: At baseline, patients had a median VF MD of -10.18 dB and mean cRNFL of 54.55±3.42 μm. The rate of change for MD and VF index were significant. No significant rate of change was noted for cRNFL, whereas significant (P < 0.001) rates were detected for GCIPL (-0.57±0.05 μm/year) and ONH parameters such as rim area (-0.010±0.001 mm Conclusions: Macula GCIPL and ONH parameters may be useful in tracking progression in patients with advanced glaucoma.
MeSH term(s)	Aged ; Disease Progression ; Female ; Follow-Up Studies ; Glaucoma, Open-Angle/diagnosis ; Glaucoma, Open-Angle/physiopathology ; Humans ; Intraocular Pressure/physiology ; Macula Lutea/diagnostic imaging ; Macula Lutea/pathology ; Male ; Middle Aged ; Nerve Fibers/pathology ; Optic Disk/diagnostic imaging ; Optic Disk/pathology ; Optic Nerve Diseases/diagnosis ; Optic Nerve Diseases/physiopathology ; Retinal Ganglion Cells/pathology ; Tomography, Optical Coherence ; Visual Acuity/physiology ; Visual Field Tests ; Visual Fields/physiology
Language	English
Publishing date	2018-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	392083-5
ISSN	1549-4713 ; 0161-6420
ISSN (online)	1549-4713
ISSN	0161-6420
DOI	10.1016/j.ophtha.2018.05.020
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Article ; Online: A randomized, feasibility trial of an exercise and nutrition-based rehabilitation programme (ENeRgy) in people with cancer.

Hall, Charlie C / Skipworth, Richard J E / Blackwood, Honor / Brown, Duncan / Cook, Jane / Diernberger, Katharina / Dixon, Elizabeth / Gibson, Valerie / Graham, Catriona / Hall, Peter / Haraldsdottir, Erna / Hopkinson, Jane / Lloyd, Anna / Maddocks, Matthew / Norris, Lucy / Tuck, Sharon / Fallon, Marie T / Laird, Barry J A

Journal of cachexia, sarcopenia and muscle

2021 Volume 12, Issue 6, Page(s) 2034–2044

Abstract: Background: Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would ... ...

Abstract	Background: Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would support an approach that targets these factors. This trial aimed to assess the feasibility of an exercise and nutrition based rehabilitation programme in people with incurable cancer. Methods: We randomized community dwelling adults with incurable cancer to either a personalized exercise and nutrition based programme (experimental arm) or standard care (control arm) for 8 weeks. Endpoints included feasibility, quality of life, physical activity (step count), and body weight. Qualitative and health economic analyses were also included. Results: Forty-five patients were recruited (23 experimental arm, 22 control arm). There were 26 men (58%), and the median age was 78 years (IQR 69-84). At baseline, the median BMI was 26 kg/m Conclusions: An exercise and nutritional rehabilitation intervention is feasible and has potential benefits for people with incurable cancer. A larger trial is now warranted to test the efficacy of this approach.
MeSH term(s)	Aged ; Aged, 80 and over ; Exercise ; Feasibility Studies ; Humans ; Male ; Neoplasms/therapy ; Nutritional Status ; Quality of Life
Language	English
Publishing date	2021-10-05
Publishing country	Germany
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2586864-0
ISSN	2190-6009 ; 2190-5991
ISSN (online)	2190-6009
ISSN	2190-5991
DOI	10.1002/jcsm.12806
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Spatial Simulation of Codesigned Land Cover Change Scenarios in New England

Jonathan R. Thompson / Joshua S. Plisinski / Kathy Fallon Lambert / Matthew J. Duveneck / Luca Morreale / Marissa McBride / Meghan Graham MacLean / Marissa Weiss / Lucy Lee

Earth's Future, Vol 8, Iss 7, Pp n/a-n/a (2020)

Alternative Futures and Their Consequences for Conservation Priorities

2020

Abstract: Abstract Scientists are increasingly engaging with stakeholders to codesign scenarios of land use change necessitating methods to translate the resulting qualitative scenarios into quantitative simulations. We demonstrate a transparent method for ... ...

Abstract	Abstract Scientists are increasingly engaging with stakeholders to codesign scenarios of land use change necessitating methods to translate the resulting qualitative scenarios into quantitative simulations. We demonstrate a transparent method for translating participatory scenarios to simulations of land use and land cover (LULC) change using the New England Landscape Futures (NELF) project as a case study. The NELF project codesigned four divergent narrative scenarios that contrast with a Recent Trends scenario projecting a continuation of observed changes New England over the past 20 years. Here, we (1) describe the process and utility of translating qualitative scenarios into spatial simulations using a dynamic cellular land change model, (2) evaluate scenario LULC configuration relative to the Recent Trends scenario and to each other, (3) compare the fate of forests within stakeholder‐defined areas of concern, and (4) describe how a user‐inspired outreach tool was developed to make the simulations and analyses accessible to a diverse user group. The associated simulations are strongly divergent in terms of the amount of LULC change and the spatial pattern of change. Among the scenarios, there is a fivefold difference in the amount of high‐density development and a twofold difference in the amount of protected land. Features of the simulations can clearly be linked back to the original storylines. Overall, the rate of LULC change has a greater influence on stakeholder areas of concern than the spatial configuration. The simulated scenarios have been integrated into an online mapping tool via a user‐engagement process meeting the needs of a variety of stakeholders.
Keywords	Scenarios ; SImulation ; Land use ; Environmental sciences ; GE1-350 ; Ecology ; QH540-549.5
Subject code	710
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The flexibility of ACE2 in the context of SARS-CoV-2 infection

Barros, Emilia P. / Casalino, Lorenzo / Gaieb, Zied / Dommer, Abigail C / Wang, Yuzhang / Fallon, Lucy / Raguette, Lauren / Belfon, Kellon / Simmerling, Carlos L. / Amaro, Rommie E.

bioRxiv

Abstract: The COVID-19 pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine developments efforts are underway, many questions remain outstanding on the mechanism ...

Abstract	The COVID-19 pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine developments efforts are underway, many questions remain outstanding on the mechanism of SARS-CoV-2 viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and entry in the cell. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular Spike glycoprotein and at the receptor binding domain-receptor interface, suggesting a role in infection. Here, we perform all-atom molecular dynamics simulations of the glycosylated, full-length membrane-bound ACE2 receptor, in both an apo and spike receptor binding domain (RBD) bound state, in order to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix, while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer, and suggests a mechanical contribution of the host receptor towards the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can be exploited for the rational design of effective SARS-CoV-2 therapeutics.
Keywords	covid19
Language	English
Publishing date	2020-09-16
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.09.16.300459
Database	COVID19

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Article: A randomised, phase II, unblinded trial of an Exercise and Nutrition-based Rehabilitation programme (ENeRgy) versus standard care in patients with cancer: feasibility trial protocol.

Hall, Charlie C / Norris, Lucy / Dixon, Liz / Cook, Jane / Maddocks, Matthew / Graham, Catriona / Tuck, Sharon / Haraldsdottir, Erna / Brown, Duncan / Lloyd, Anna / Finucane, Anne / Hall, Peter / Diernberger, Katharina / Skipworth, Richard J E / Fallon, Marie / Laird, Barry J

Pilot and feasibility studies

2018 Volume 4, Page(s) 192

Language	English
Publishing date	2018-12-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2809935-7
ISSN	2055-5784
ISSN	2055-5784
DOI	10.1186/s40814-018-0381-6
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Article ; Online: A randomised, phase II, unblinded trial of an Exercise and Nutrition-based Rehabilitation programme (ENeRgy) versus standard care in patients with cancer

Charlie C. Hall / Lucy Norris / Liz Dixon / Jane Cook / Matthew Maddocks / Catriona Graham / Sharon Tuck / Erna Haraldsdottir / Duncan Brown / Anna Lloyd / Anne Finucane / Peter Hall / Katharina Diernberger / Richard J. E. Skipworth / Marie Fallon / Barry J. Laird

Pilot and Feasibility Studies, Vol 4, Iss 1, Pp 1-

feasibility trial protocol

2018 Volume 6

Keywords	Medicine (General) ; R5-920
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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