The role of circular dichroism spectroscopy in the era of integrative structural biology

Abstract

Circular dichroism (CD) spectroscopy has been used widely in structural biology for literally a half century, primarily to examine the secondary structure, folding and interactions of proteins in solution. With recent developments in instrumentation, it is now possible to apply CD to many additional types of sample environments, including oriented membranes, films, and dehydrated samples. In addition, developments in bioinformatics have made validated CD spectra and metadata available for novel analysis methods on additional types of samples such as membrane proteins, intrinsically disordered proteins, multiple fold types, and multicomponent, macromolecular complexes. New software has also enabled increased inter-operability of CD with other structural biology methodologies, contributing to their use in joint studies of protein structures at various levels of organization. Highlights:• Instrumentation developments are enabling an enhanced range of measurements • The PCDDB provides spectra and metadata for traceability and methods development • New software developments are enabling novel types of analyses • CD spectroscopy can now examine more types of proteins with important biological roles • CD spectroscopy is being used in many interdisciplinary and structural biology applications Introduction:This review focuses on new developments in electronic circular dichroism (CD) spectroscopy of proteins. CD is a well-established technique that has recently gained popularity due to developments in data archiving, validation, analyses, and types of samples that can be studied due to new instrumentation (such as synchrotron radiation circular dichroism (SRCD)). CD is now finding use as one of a cadre of methods that can be used to examine the structure, dynamics and similarities of different individual proteins, macromolecular complexes, and protein families. Indeed, a noticeable trend is not only the growth in the number of studies using CD, but in how many of them use CD in conjunction with other methods as part of integrative programs in structural biology. In the past 5 years, more than one-third of the published papers incorporating CD studies of proteins also used another structural biology technique (such as X-ray crystallography, electron cryomicroscopy (cryoEM), nuclear magnetic resonance (NMR) spectroscopy, small angle X-ray and neutron scattering, or molecular dynamics and computational modeling). The interrelationships between these methods have been enhanced during this time period due to new developments in CD data accessibility and bioinformatics that are described in this review. New Instrumentation Enabling Spectroscopic Measurements:In recent years instrumentation developments have enabled new and improved CD spectroscopic measurements. The most notable of these developments has been SRCD, in which ultraviolet (UV) and vacuum UV wavelength radiation produced by a synchrotron is used

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“…Circular dichroism (CD) spectroscopy is a simple, nondestructive optical technique that is most sensitive to the structural polymorphism of nucleic acids (1). Although CD cannot provide atomic-level structural insights about the nucleic acids like Xray crystallography and NMR-spectroscopy, it has its own advantage in terms of quickness in providing the secondary structural information from a low sample concentration (7,11,12).…”

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“…Biophysical methodologies will continue to be highly important in the study of MBP and IDPs in general. CD and NMR spectroscopy are powerful tools in directly probing disorder [278,279]. Small-angle scattering methods are sensitive to aggregation, but useful in probing conformational sampling in solution [280], complementing for example Förster resonance energy transfer experiments and computational methods [281,282].…”

Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease

“…Biophysical methodologies will continue to be highly important in the study of MBP and IDPs in general. CD and NMR spectroscopy are powerful tools in directly probing disorder [274,275]. Small-angle scattering methods are sensitive to aggregation, but useful in probing conformational sampling in solution [276], complementing especially Förster resonance energy transfer experiments and computational methods [277,278].…”