“… Figure 2 A large conformational change of CXCR4 occurs during a 180 ns aMD trajectory. ( a ) Time evolution of (from top to bottom): the RMSD of all the Cα atoms of the receptor (black line) and of the transmembrane domain only (grey lines); the distance between TM3 and TM6, measured as the distance between the Cα atoms of residues R134 3 . 50 and K234 6 .…”
Section: Resultsmentioning
confidence: 99%
“…2 b), the sodium ion was tightly bound to its canonical site 33 that is formed by one water molecule and four protein atoms: the Oδ1 atom of D84 2 . 50 , the Oδ1 atom of N119 3 . 35 , the Oγ atom of S123 3 .…”
Section: Resultsmentioning
confidence: 99%
“…Collective motions have larger amplitude and lead to larger domain motions that may occur on the microsecond to second or larger timescale. The experimental techniques developed to access these motions can be complemented by molecular dynamics (MD) simulations that provide a dynamic view of protein structures 3 – 7 .…”
The dynamic structure of proteins is essential for their functions and may include large conformational transitions which can be studied by molecular dynamics (MD) simulations. However, details of these transitions are difficult to automatically track. To facilitate their analysis, we developed two scores of correlation between sidechain dihedral angles. The CIRCULAR and OMES scores are computed from, respectively, dihedral angle values and rotamer distributions. As a case study, we applied our methods to an activation-like transition of the chemokine receptor CXCR4, observed during accelerated MD simulations. The principal component analysis of the correlation matrices was consistent with the networking structure of the top ranking pairs. Both scores identify a set of residues whose “collaborative” sidechain rotamerization immediately preceded or accompanied the conformational transition of CXCR4. Detailed analysis of the sequential order of these rotamerizations suggests that an allosteric mechanism, involving the outward motion of an asparagine residue in transmembrane helix 3, might be a prerequisite to the large scale conformational transition of CXCR4. This case study provides the proof-of-concept that the correlation methods developed here are valuable exploratory techniques to help decipher complex reactional pathways.
“… Figure 2 A large conformational change of CXCR4 occurs during a 180 ns aMD trajectory. ( a ) Time evolution of (from top to bottom): the RMSD of all the Cα atoms of the receptor (black line) and of the transmembrane domain only (grey lines); the distance between TM3 and TM6, measured as the distance between the Cα atoms of residues R134 3 . 50 and K234 6 .…”
Section: Resultsmentioning
confidence: 99%
“…2 b), the sodium ion was tightly bound to its canonical site 33 that is formed by one water molecule and four protein atoms: the Oδ1 atom of D84 2 . 50 , the Oδ1 atom of N119 3 . 35 , the Oγ atom of S123 3 .…”
Section: Resultsmentioning
confidence: 99%
“…Collective motions have larger amplitude and lead to larger domain motions that may occur on the microsecond to second or larger timescale. The experimental techniques developed to access these motions can be complemented by molecular dynamics (MD) simulations that provide a dynamic view of protein structures 3 – 7 .…”
The dynamic structure of proteins is essential for their functions and may include large conformational transitions which can be studied by molecular dynamics (MD) simulations. However, details of these transitions are difficult to automatically track. To facilitate their analysis, we developed two scores of correlation between sidechain dihedral angles. The CIRCULAR and OMES scores are computed from, respectively, dihedral angle values and rotamer distributions. As a case study, we applied our methods to an activation-like transition of the chemokine receptor CXCR4, observed during accelerated MD simulations. The principal component analysis of the correlation matrices was consistent with the networking structure of the top ranking pairs. Both scores identify a set of residues whose “collaborative” sidechain rotamerization immediately preceded or accompanied the conformational transition of CXCR4. Detailed analysis of the sequential order of these rotamerizations suggests that an allosteric mechanism, involving the outward motion of an asparagine residue in transmembrane helix 3, might be a prerequisite to the large scale conformational transition of CXCR4. This case study provides the proof-of-concept that the correlation methods developed here are valuable exploratory techniques to help decipher complex reactional pathways.
“…Moreover,f luorine is emerging as av ery interesting probe to study protein structure and biomolecular interactions, thanks to the very interesting features of 19 FNMR. [63,64]…”
Section: Applications Of Ssilmentioning
confidence: 99%
“…For example, some amino acids are post ‐translationally methylated (arginine and lysine) or hydroxylated (proline and lysine), playing important roles in signaling and regulation. Moreover, fluorine is emerging as a very interesting probe to study protein structure and biomolecular interactions, thanks to the very interesting features of 19 F NMR …”
Remarkable technical progress in the area of structural biology has paved the way to study previously inaccessible targets. For example, large protein complexes can now be easily investigated by cryo‐electron microscopy, and modern high‐field NMR magnets have challenged the limits of high‐resolution characterization of proteins in solution. However, the structural and dynamic characteristics of certain proteins with important functions still cannot be probed by conventional methods. These proteins in question contain low‐complexity regions (LCRs), compositionally biased sequences where only a limited number of amino acids is repeated multiple times, which hamper their characterization. This Concept article describes a site‐specific isotopic labeling (SSIL) strategy, which combines nonsense suppression and cell‐free protein synthesis to overcome these limitations. An overview on how poly‐glutamine tracts were made amenable to high‐resolution structural studies is used to illustrate the usefulness of SSIL. Furthermore, we discuss the potential of this methodology to give further insights into the roles of LCRs in human pathologies and liquid–liquid phase separation, as well as the challenges that must be addressed in the future for the popularization of SSIL.
βγ-Crystallins are the primary structural and refractive proteins found in the vertebrate eye lens. Because crystallins are not replaced after early eye development, their solubility and stability must be maintained for a lifetime, which is even more remarkable given the high protein concentration in the lens. Aggregation of crystallins caused by mutations or post-translational modifications can reduce crystallin protein stability and alter intermolecular interactions. Common post-translational modifications that can cause age-related cataracts include deamidation, oxidation, and tryptophan derivatization. Metal ion binding can also trigger reduced crystallin solubility through a variety of mechanisms. Interprotein interactions are critical to maintaining lens transparency: crystallins can undergo domain swapping, disulfide bonding, and liquid-liquid phase separation, all of which can cause opacity depending on the context. Important experimental techniques for assessing crystallin conformation in the absence of a high-resolution structure include dye-binding assays, circular dichroism, fluorescence, light scattering, and transition metal FRET.
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