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Highlights of Coronavirus Structural Studies

12 Jul 2021

The Contribution of Biophysics and Structural Biology to Current Advances in COVID-19 (Annual reviews of Biophysics)

Critical to viral infection are the multiple interactions between viral proteins and host-cell counterparts. The first such interaction is the recognition of viral envelope proteins by surface receptors that normally fulfil other physiological roles, a hijacking mechanism perfected over the course of evolution. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), has successfully adopted this strategy using its spike glycoprotein to dock on the membrane-bound metalloprotease angiotensin-converting enzyme 2 (ACE2). The crystal structures of several SARS-CoV-2 proteins alone or in complex with their receptors or other ligands were recently solved at an unprecedented pace. This accomplishment is partly due to the increasing availability of data on other coronaviruses and ACE2 over the past 18 years. Likewise, other key intervening actors and mechanisms of viral infection were elucidated with the aid of biophysical approaches. An understanding of the various structurally important motifs of the interacting partners provides key mechanistic information for the development of structure-based designer drugs able to inhibit various steps of the infective cycle, including neutralizing antibodies, small organic drugs, and vaccines. This review analyzes current progress and the outlook for future structural studies.

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Reader's Corner Archive

12 Mar 2021

Solid-state NMR spectroscopy (Nature Reviews Methods Primers)

Solid-state nuclear magnetic resonance (NMR) spectroscopy is an atomic-level method to determine the chemical structure, 3D structure and dynamics of solids and semi-solids. This Primer summarizes the basic principles of NMR spectroscopy as applied to the wide range of solid systems. The nuclear spin interactions and the effects of magnetic fields and radiofrequency pulses on nuclear spins in solid-state NMR are the same as in liquid-state NMR spectroscopy. However, because of the orientation dependence of the nuclear spin interactions in the solid state, the majority of high-resolution solid-state NMR spectra are measured under magic-angle spinning (MAS), which has profound effects on the types of radiofrequency pulse sequences required to extract structural and dynamical information. Mei Hong et. al. describe the most common MAS NMR experiments and data analysis approaches for investigating biological macromolecules, organic materials and inorganic solids. Continuing development of sensitivity-enhancement NMR approaches, including 1H-detected fast MAS experiments, dynamic nuclear polarization and experiments in ultra-high magnetic fields, is described. They highlight recent applications of solid-state NMR spectroscopy to biological and materials chemistry. The Primer ends with a discussion of current limitations as well as areas of development of solid-state NMR spectroscopy and points to emerging areas of applications of this sophisticated spectroscopy.

19 Feb 2021

Computational modeling of dynein motor proteins at work (Chem. Commun.)

Along with various experimental methods, a combination of theoretical and computational methods is essential to explore different length-scale and time-scale processes in the biological system. The functional mechanism of a dynein, an ATP-fueled motor protein, working in a multiprotein complex, involves a wide range of length/time-scale events. It generates mechanical force from chemical energy and moves on microtubules towards the minus end direction while performing a large number of biological processes including ciliary beating, intracellular material transport, and cell division. Like in the cases of other conventional motor proteins, a combination of experimental techniques including X-crystallography, cryo-electron microscopy, and single molecular assay have provided a wealth of information about the mechanochemical cycle of a dynein. Dyneins have a large and complex structural architecture and therefore, computational modeling of different aspects of a dynein is extremely challenging. As the process of dynein movement involves varying length and timescales, it demands, like in experiments, a combination of computational methods covering such a wide range of processes for the comprehensive investigation of the mechanochemical cycle. In this review article, M. Dutta and B.Jama summarize how the use of state-of-the-art computational methods can provide a detailed molecular understanding of the mechanochemical cycle of the dynein. They implemented all-atom molecular dynamics simulations and hybrid quantum-mechanics/molecular-mechanics simulations to explore the ATP hydrolysis mechanisms at the primary ATPase site (AAA1) of dynein. To investigate the large-scale conformational changes They employed coarse-grained structure-based molecular dynamics simulations to capture the domain motions. Here they explored the conformational changes upon binding of ATP at AAA1, nucleotide state-dependent regulation of the mechanochemical cycle, and inter-head coordination by inter-head tension. Additionally, implementing a phenomenological theoretical model we explore the force-dependent detachment rate of a motorhead from the microtubule and the principle of multi-dynein cooperation during cargo transport.

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