Exploring the conformational heterogeneity of biomolecules: theory and experiments
This themed collection reports on recent progress in the investigation of the conformational variability of biomolecules (proteins and nucleic acids), both from an experimental and theoretical point of view.
A critical assessment of methods to recover information from averaged data
We analyze the different approaches to obtain quantitative and accurate structural information from averaged data. We cluster them in two groups: those satisfying the maximum entropy principle and those recovering ensembles composed of a restricted number of conformations. Information of different types are recovered in the two cases.
Conformational ensemble of human α-synuclein physiological form predicted by molecular simulations
Enhanced sampling simulations of N-terminally acetylated human α-synuclein suggest that the post-translational modification leads to the formation of a transient amphipathic α-helix altering protein dynamics at the N-terminal and intramolecular interactions.
Investigation of the structural preference and flexibility of the loop residues in amyloid fibrils of the HET-s prion
The structural variability of HET-s(218–289) loops is restricted by the β-sheet core.
Analysis of the solution conformations of T4 lysozyme by paramagnetic NMR spectroscopy
Paramagnetic data show that the average structure of T4-lysozyme in solution is more open than its crystal structure.
Dynamics of GCN4 facilitate DNA interaction: a model-free analysis of an intrinsically disordered region
Intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered regions (IDRs) are known to play important roles in regulatory and signaling pathways.
Paper
Deciphering conformational transitions of proteins by small angle X-ray scattering and normal mode analysis
SREFLEX employs normal mode analysis for the flexible refinement of atomic models of biological macromolecules against solution scattering data, providing insight into conformational transitions.
Paper
Bayesian inference of protein ensembles from SAXS data
A probabilistic method infers ensembles of intrinsically disordered proteins (IDPs) by combining SAXS data with a force field.
Pulsed EPR characterization of HIV-1 protease conformational sampling and inhibitor-induced population shifts
The conformational landscape of HIV-1 protease can be characterized by double electron–electron resonance (DEER) spin-labeling.
Insights into the allosteric regulation of Syk association with receptor ITAM, a multi-state equilibrium
Syk high-affinity association with receptor ITAM is regulated by a phosphorylation-dependent allosteric mechanism. NMR titration-curve/line-shape analyses determined phosphorylation increases the energetic barrier for, but does not prevent, isomerization.
Paper
The use of the Rx spin label in orientation measurement on proteins, by EPR
Alternative labeling sites using the ‘rigid’ Rx spin label on protein secondary structures are explored and high field orientation measurements are made.
Multi-probe relaxation dispersion measurements increase sensitivity to protein dynamics
Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion measurements are a valuable tool for the characterization of structural transitions on the micro-millisecond timescale.
Linkage-specific conformational ensembles of non-canonical polyubiquitin chains
Ensemble analysis using NMR and SANS revealed conformational heterogeneity of polyubiquitin chains, suggesting unique as well as overlapping functions.
Quantitative evaluation of positive ϕ angle propensity in flexible regions of proteins from three-bond J couplings
3 J C′Hα couplings in disordered proteins allow quantitative evaluation of the fraction of time each residue adopts a positive ϕ backbone angle.
Paper
Detection of correlated conformational fluctuations in intrinsically disordered proteins through paramagnetic relaxation interference
NMR-based paramagnetic relaxation interference (PRI) allows for direct observation of concerted motions and cooperatively folded sub-states in IDPs, via cross correlated relaxation.
Inter-helical conformational preferences of HIV-1 TAR-RNA from maximum occurrence analysis of NMR data and molecular dynamics simulations
Molecular dynamics simulations and maximum occurrence distribution identify the same most likely sampled conformations over the available conformational space.
Paper
Protein docking using an ensemble of spin labels optimized by intra-molecular paramagnetic relaxation enhancement
The effect of spin label mobility on the accuracy of protein–protein docking calculations was investigated using inter- and intra-molecular PRE data.
Evolution of magnetization due to asymmetric dimerization: theoretical considerations and application to aberrant oligomers formed by apoSOD12SH
A set of coupled differential equations is presented describing the evolution of magnetization due to an exchange reaction whereby a pair of identical monomers form an asymmetric dimer.
About this collection
This themed issue reports recent progress in the investigation of the conformational variability of biomolecules (proteins and nucleic acids), both from the experimental and the theoretical point of view.
Many biochemical processes rely on the ability of one or more of the participating molecules to adopt different conformations, while retaining some structural specificity. Sampling multiple conformational states often leads to the averaging of the experimental observables, and average experimental observables can be accounted for by an infinite number of different conformational ensembles. Significant progress has been made in understanding the conformational heterogeneity of molecules with a degree of internal flexibility, for example: two-domain proteins, IDPs, protein complexes and RNA. This issue demonstrates the potential of a wide range of techniques that can be used to address the problem of characterisation of dynamic properties of biomolecules. The contributions move beyond conventional descriptions in terms of static structures, and towards the characterisation of population-weighted ensembles in which the system is described by a distribution of many conformations.
The guest editor for this themed issue is Claudio Luchinat (University of Florence, Italy).