Capturing a dynamically interacting inhibitor by paramagnetic NMR spectroscopy

Physical Chemistry Chemical Physics : PCCP
Pavel SrbVáclav Veverka

Abstract

Transient and fuzzy intermolecular interactions are fundamental to many biological processes. Despite their importance, they are notoriously challenging to characterize. Effects induced by paramagnetic ligands in the NMR spectra of interacting biomolecules provide an opportunity to amplify subtle manifestations of weak intermolecular interactions observed for diamagnetic ligands. Here, we present an approach to characterizing dynamic interactions between a partially flexible dimeric protein, HIV-1 protease, and a metallacarborane-based ligand, a system for which data obtained by standard NMR approaches do not enable detailed structural interpretation. We show that for the case where the experimental data are significantly averaged to values close to zero the standard fitting of pseudocontact shifts cannot provide reliable structural information. We based our approach on generating a large ensemble of full atomic models, for which the experimental data can be predicted, ensemble averaged and finally compared to the experiment. We demonstrate that a combination of paramagnetic NMR experiments, quantum chemical calculations, and molecular dynamics simulations offers a route towards structural characterization of dynamic protein-li...Continue Reading

References

Nov 5, 1965·Journal of the American Chemical Society·M F HawthorneP A Wegner
Jul 1, 1993·Archives of Biochemistry and Biophysics·P MajerP Strop
Oct 28, 1996·Physical Review Letters·J P PerdewM Ernzerhof
Feb 5, 2003·Journal of Magnetic Resonance·Charles D SchwietersG Marius Clore
Jan 31, 2004·Journal of Biomolecular NMR·Lucia BanciGiacomo Parigi
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Aug 12, 2005·Chembiochem : a European Journal of Chemical Biology·Ivano BertiniRoberta Pierattelli
Oct 18, 2005·Proceedings of the National Academy of Sciences of the United States of America·Petr CíglerJan Konvalinka
Feb 4, 2006·Journal of Biomolecular NMR·Vaclav VeverkaMark D Carr
Feb 7, 2006·Journal of Molecular Graphics & Modelling·Junmei WangDavid A Case
Jun 13, 2006·Journal of Biomolecular NMR·Christophe SchmitzThomas Huber
Sep 28, 2006·Journal of the American Chemical Society·Michael JohnGottfried Otting
Oct 13, 2006·Journal of Structural Biology·Valentina TozziniJ Andrew McCammon
Nov 23, 2006·Journal of the American Chemical Society·Stéphane BalayssacMario Piccioli
Apr 29, 2008·Journal of the American Chemical Society·Xingfu XuMarcellus Ubbink
Jun 17, 2009·Journal of Biomolecular NMR·Xun-Cheng Su, Gottfried Otting
Feb 6, 2010·British Journal of Pharmacology·Edward C Hulme, Mike A Trevethick
May 14, 2010·Annual Review of Biophysics·Gottfried Otting
May 27, 2010·Journal of the American Chemical Society·Loïc SalmonMartin Blackledge
Oct 15, 2010·The Journal of Chemical Physics·Dmitrij Rappoport, Filipp Furche
Jan 19, 2011·Progress in Nuclear Magnetic Resonance Spectroscopy·Peter H J Keizers, Marcellus Ubbink
Feb 4, 2012·Journal of the American Chemical Society·Alexandar L HansenLewis E Kay
Apr 11, 2012·Inorganic Chemistry·Khadga KarkiDanilo Roccatano
May 5, 2012·Journal of the American Chemical Society·Pramodh VallurupalliLewis E Kay
Jul 23, 2013·Chembiochem : a European Journal of Chemical Biology·Veronika PapouškováLukáš Žídek
Aug 22, 2013·Progress in Nuclear Magnetic Resonance Spectroscopy·Mike P Williamson
Dec 7, 2013·Angewandte Chemie·Jiří BryndaPavlína Řezáčová
Apr 12, 2014·Current Opinion in Structural Biology·Mathias A S Hass, Marcellus Ubbink
Aug 21, 2015·Journal of the American Chemical Society·Ulrika BrathMáté Erdélyi
Nov 18, 2015·Journal of Chemical Theory and Computation·Juha VaaraJiří Mareš
Dec 18, 2015·The Journal of Biological Chemistry·Georg KünzeDaniel Huster
Feb 14, 2016·Chemical Biology & Drug Design·Mukul MahantiPär Söderhjelm
Apr 26, 2016·Scientific Reports·Christopher A WaudbyJohn Christodoulou
Oct 7, 2016·Physical Chemistry Chemical Physics : PCCP·Elizaveta A Suturina, Ilya Kuprov

❮ Previous
Next ❯

Citations

Jan 10, 2020·Journal of Biomolecular NMR·Christopher A WaudbyJohn Christodoulou
Nov 13, 2020·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Jindřich FanfrlíkPavel Hobza
Apr 3, 2021·Frontiers in Molecular Biosciences·Changkai Bu, Lan Jin
Jun 11, 2019·The Journal of Physical Chemistry Letters·Linda CerofoliniClaudio Luchinat
Jan 11, 2022·Chemical Reviews·Thomas MüntenerSebastian Hiller

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray
NMR
chemical exchange saturation transfer
chemical modifications

Software Mentioned

TURBOMOLE
GAFF
PyMol
TITAN
AMBER14
CHIMERA
Sparky
OCTAVE

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.