G. Marius Clore MAE, FRSC, FMedSci, FRS is a British-born, Anglo-American molecular biophysicist and structural biologist. He was born in London, U.K. and is a dual U.S./U.K. Citizen. [1] [2] [3] He is a Member of the National Academy of Sciences, [4] a Fellow of the Royal Society, [5] a Fellow of the Academy of Medical Sciences, a Fellow of the American Academy of Arts and Sciences, a NIH Distinguished Investigator, and the Chief of the Molecular and Structural Biophysics Section in the Laboratory of Chemical Physics of the National Institute of Diabetes and Digestive and Kidney Diseases at the U.S. National Institutes of Health. [6] [7] He is known for his foundational work in three-dimensional protein and nucleic acid structure determination by biomolecular NMR spectroscopy, [8] for advancing experimental approaches to the study of large macromolecules and their complexes by NMR, [9] and for developing NMR-based methods to study rare conformational states in protein-nucleic acid [10] and protein-protein [11] recognition. [12] Clore's discovery of previously undetectable, functionally significant, rare transient states of macromolecules has yielded fundamental new insights into the mechanisms of important biological processes, and in particular the significance of weak interactions and the mechanisms whereby the opposing constraints of speed and specificity are optimized. Further, Clore's work opens up a new era of pharmacology and drug design as it is now possible to target structures and conformations that have been heretofore unseen. [13]
Clore received his undergraduate degree with first class honours in biochemistry from University College London in 1976 and medical degree from UCL Medical School in 1979. [4] After completing house physician and house surgeon appointments at University College Hospital and St Charles' Hospital (part of the St. Mary's Hospital group), respectively, he was a member of the scientific staff of the Medical Research Council National Institute for Medical Research from 1980 to 1984. He received his PhD from the National Institute for Medical Research in Physical Biochemistry in 1982. He was awarded a joint Lister Institute Research Fellowship from the Lister Institute of Preventive Medicine which he held from 1982 to 1984 at the Medical Research Council. [14] In 1984 he joined the Max Planck Institute for Biochemistry in Martinsried, Germany, where he headed the Biological NMR department from 1984 to 1988. [1] [2]
In 1988, Clore was recruited to the National Institutes of Health (NIH) Laboratory of Chemical Physics (National Institute of Diabetes and Digestive and Kidney Diseases) located in Bethesda, Maryland, U.S., where he interacted closely in the late 1980s and early 1990s with NIH colleagues Ad Bax, Angela Gronenborn and Dennis Torchia on the development of multidimensional heteronuclear NMR spectroscopy and a structural biology effort aimed at proteins involved in the pathogenesis of HIV/AIDS. [15] He has remained at the NIH ever since and is currently a NIH Distinguished Investigator and Chief of the Section on Molecular and Structural Biophysics at the NIH. [4] He is an elected Member of the United States National Academy of Sciences, [16] a Fellow of the Royal Society, [17] a Fellow of the American Academy of Arts and Sciences, [18] [19] and a Foreign Member of the Academia Europaea (Biochemistry and Molecular Biology Section). [20] Clore's citation upon election to the Royal Society reads:
"Clore pioneered the development of NMR for determining three-dimensional structures of biological macromolecules and has consistently extended the frontiers of NMR to ever more complex systems. His work on the development of paramagnetic and other relaxation-based NMR experiments to detect and visualize transient, rare states of macromolecules, invisible to conventional structural and biophysical techniques, has shed unique insights into how macromolecules efficiently locate their binding partners, provided the first atomic view of the dynamic amyloid Aß assembly process from disordered peptides into protofibrils, and directly demonstrated that the apo state of the chaperonin GroEL possesses intrinsic foldase/unfoldase activities." [5]
Clore played a pivotal role in the development of three- and four-dimensional NMR spectroscopy, [21] the use of residual dipolar couplings for structure determination, [22] the development of simulated annealing and restrained molecular dynamics for three-dimensional protein and nucleic acid structure determination, [23] the solution NMR structure determination of large protein complexes, [24] the development of the combined use of NMR and small-angle X-ray scattering in solution structure determination, [25] and the analysis and characterization of protein dynamics by NMR. [26] Clore's work on complexes of all the cytoplasmic components of the bacterial phosphotransferase system (PTS) led to significant insights into how signal transduction proteins recognize multiple, structurally dissimilar partners by generating similar binding surfaces from completely different structural elements and exploiting side chain conformational plasticity. [24] Clore is also one of the main authors of the very widely used XPLOR-NIH NMR structure determination program [27]
Clore's recent work has focused on developing new NMR methods (such as paramagnetic relaxation enhancement, dark state exchange saturation transfer spectroscopy and lifetime line broadening) to detect, characterize and visualize the structure and dynamics of sparsely-populated states of macromolecules, which are important in macromolecular interactions but invisible to conventional structural and biophysical techniques. [28] Examples of include the direct demonstration of rotation-coupled sliding and intermolecular translocation as mechanisms whereby sequence-specific DNA binding proteins locate their target site(s) within an overwhelming sea of non-specific DNA sequences; [29] the detection, visualization and characterization of encounter complexes in protein-protein association; [30] the analysis of the synergistic effects of conformational selection and induced fit in protein-ligand interactions; [31] and the uncovering of "dark", spectroscopically invisible states in interactions of NMR-visible proteins and polypeptides (including intrinsically disordered states) with very large megadalton macromolecular assemblies. [32] The latter includes an atomic-resolution view of the dynamics of the amyloid-β aggregation process. [33] and the demonstration of intrinsic unfoldase/foldase activity of the macromolecular machine GroEL. [34] These various techniques have also been used to uncover the kinetic pathway of pre-nucleation transient oligomerization events and associated structures involving the protein encoded by huntingtin exon-1, which may provide a potential avenue for therapeutic intervention in Huntington's disease, a fatal autosomal dominant, neurodegenerative condition. [35] [36]
Clore is one of the most highly cited scientists in the fields of molecular biophysics, structural biology, biomolecular NMR and chemistry [37] [38] with over 550 published scientific articles and an h-index (number of papers cited h or more time) of 144. [39] Clore is also one of only four NIH scientists to have been elected to both the United States National Academy of Sciences and The Royal Society, the other three being Julius Axelrod, Francis Collins and Harold Varmus.
Marius Clore was educated at the Lycee Francais Charles de Gaulle in Kensington, London, University College London and UCL Medical School. Marius Clore's father was the film producer Leon Clore whose credits include The French Lieutenant's Woman.
Structural biology, as defined by the Journal of Structural Biology, deals with structural analysis of living material at every level of organization.
A spin label (SL) is an organic molecule which possesses an unpaired electron, usually on a nitrogen atom, and the ability to bind to another molecule. Spin labels are normally used as tools for probing proteins or biological membrane-local dynamics using electron paramagnetic resonance spectroscopy. The site-directed spin labeling (SDSL) technique allows one to monitor a specific region within a protein. In protein structure examinations, amino acid-specific SLs can be used.
Nuclear magnetic resonance spectroscopy of proteins is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and their complexes. The field was pioneered by Richard R. Ernst and Kurt Wüthrich at the ETH, and by Ad Bax, Marius Clore, Angela Gronenborn at the NIH, and Gerhard Wagner at Harvard University, among others. Structure determination by NMR spectroscopy usually consists of several phases, each using a separate set of highly specialized techniques. The sample is prepared, measurements are made, interpretive approaches are applied, and a structure is calculated and validated.
Xplor-NIH is a highly sophisticated and flexible biomolecular structure determination program which includes an interface to the legacy X-PLOR program. The main developers are Charles Schwieters and Marius Clore of the National Institutes of Health. Xplor-NIH is based on a C++ framework with an extensive Python interface enabling very powerful and easy scripting of complex structure determination and refinement protocols. Restraints derived from all current solution and many solid state nuclear magnetic resonance (NMR) and X-ray scattering experiments can be accommodated during structure calculations. Extensive facilities are also available for many types of ensemble calculations where the experimental data cannot be accounted for by a unique structure. Many of the structure calculation protocols involve the use of simulated annealing designed to overcome local minima on the path of the global minimum region of the target function. These calculations can be carried out using any combination of Cartesian, torsion angle and rigid body dynamics and minimization. Currently Xplor-NIH is the most versatile, comprehensive and widely used structure determination/refinement package in NMR structure determination.
Frederic Middlebrook Richards, commonly referred to as Fred Richards, was an American biochemist and biophysicist known for solving the pioneering crystal structure of the ribonuclease S enzyme in 1967 and for defining the concept of solvent-accessible surface. He contributed many key experimental and theoretical results and developed new methods, garnering over 20,000 journal citations in several quite distinct research areas. In addition to the protein crystallography and biochemistry of ribonuclease S, these included solvent accessibility and internal packing of proteins, the first side-chain rotamer library, high-pressure crystallography, new types of chemical tags such as biotin/avidin, the nuclear magnetic resonance (NMR) chemical shift index, and structural and biophysical characterization of the effects of mutations.
Molecular biophysics is a rapidly evolving interdisciplinary area of research that combines concepts in physics, chemistry, engineering, mathematics and biology. It seeks to understand biomolecular systems and explain biological function in terms of molecular structure, structural organization, and dynamic behaviour at various levels of complexity. This discipline covers topics such as the measurement of molecular forces, molecular associations, allosteric interactions, Brownian motion, and cable theory. Additional areas of study can be found on Outline of Biophysics. The discipline has required development of specialized equipment and procedures capable of imaging and manipulating minute living structures, as well as novel experimental approaches.
Ian Andrew Wilson is the Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at the Scripps Research Institute in San Diego, California, United States.
The residual dipolar coupling between two spins in a molecule occurs if the molecules in solution exhibit a partial alignment leading to an incomplete averaging of spatially anisotropic dipolar couplings.
Adriaan "Ad" Bax is a Dutch-American molecular biophysicist. He was born in the Netherlands and is the Chief of the Section on Biophysical NMR Spectroscopy at the National Institutes of Health. He is known for his work on the methodology of biomolecular NMR spectroscopy. He is a corresponding member of the Royal Netherlands Academy of Arts and Sciences, a member of the National Academy of Sciences, a fellow of the American Academy of Arts and Sciences, and a Foreign Member of the Royal Society.
David S. Cafiso is an American biochemist and a professor of chemistry at the University of Virginia. His research focuses on membrane proteins and cell signaling, and is primarily supported by grants from the National Institute of Health.
Jane Shelby Richardson is an American biophysicist best known for developing the Richardson diagram, or ribbon diagram, a method of representing the 3D structure of proteins. Ribbon diagrams have become a standard representation of protein structures that has facilitated further investigation of protein structure and function globally. With interests in astronomy, math, physics, botany, and philosophy, Richardson took an unconventional route to establishing a science career. Richardson is a professor in biochemistry at Duke University.
Axel T. Brunger is a German American biophysicist. He is Professor of Molecular and Cellular Physiology at Stanford University, and a Howard Hughes Medical Institute Investigator. He served as the Chair of the Department of Molecular and Cellular Physiology (2013–2017).
The term macromolecular assembly (MA) refers to massive chemical structures such as viruses and non-biologic nanoparticles, cellular organelles and membranes and ribosomes, etc. that are complex mixtures of polypeptide, polynucleotide, polysaccharide or other polymeric macromolecules. They are generally of more than one of these types, and the mixtures are defined spatially, and with regard to their underlying chemical composition and structure. Macromolecules are found in living and nonliving things, and are composed of many hundreds or thousands of atoms held together by covalent bonds; they are often characterized by repeating units. Assemblies of these can likewise be biologic or non-biologic, though the MA term is more commonly applied in biology, and the term supramolecular assembly is more often applied in non-biologic contexts. MAs of macromolecules are held in their defined forms by non-covalent intermolecular interactions, and can be in either non-repeating structures, or in repeating linear, circular, spiral, or other patterns. The process by which MAs are formed has been termed molecular self-assembly, a term especially applied in non-biologic contexts. A wide variety of physical/biophysical, chemical/biochemical, and computational methods exist for the study of MA; given the scale of MAs, efforts to elaborate their composition and structure and discern mechanisms underlying their functions are at the forefront of modern structure science.
Gabriel Waksman FMedSci, FRS, is Courtauld professor of biochemistry and molecular biology at University College London (UCL), and professor of structural and molecular biology at Birkbeck College, University of London. He is the director of the Institute of Structural and Molecular Biology (ISMB) at UCL and Birkbeck, head of the Department of Structural and Molecular Biology at UCL, and head of the Department of Biological Sciences at Birkbeck.
Dennis Torchia is an American biophysicist who specialized in NMR spectroscopy. He spent most of his career at the National Institute of Dental and Craniofacial Research (NIDCR), part of the United States National Institutes of Health, where he served as Chief of the Structural Biology Unit before his retirement in 2006.
Hartmut Oschkinat is a German structural biologist and professor for chemistry at the Free University of Berlin. His research focuses on the study of biological systems with solid-state nuclear magnetic resonance.
William Allen Eaton is a biophysical chemist who is a NIH Distinguished Investigator, Chief of the Section on Biophysical Chemistry, and Chief of the Laboratory of Chemical Physics at the National Institute of Diabetes and Digestive and Kidney Diseases, one of the 20 Institutes of the United States National Institutes of Health.
Mei Hong is a Chinese-American biophysical chemist and professor of chemistry at the Massachusetts Institute of Technology. She is known for her creative development and application of solid-state nuclear magnetic resonance (ssNMR) spectroscopy to elucidate the structures and mechanisms of membrane proteins, plant cell walls, and amyloid proteins. She has received a number of recognitions for her work, including the American Chemical Society Nakanishi Prize in 2021, Günther Laukien Prize in 2014, the Protein Society Young Investigator award in 2012, and the American Chemical Society’s Pure Chemistry award in 2003.
Julie Forman-Kay is a scientist at the Hospital for Sick Children (SickKids) and professor at University of Toronto. Her research focuses on the dynamics, interactions, structures, and functions of intrinsically disordered proteins.