Mobility is a common feature of biomacromolecules, often fundamental for their function. Thus, in many cases, biomacromolecules cannot be described by a single conformation, but rather by a conformational ensemble. NMR paramagnetic data demonstrated quite informative to monitor this conformational variability, especially when used in conjunction with data from different sources. Due to their long-range nature, paramagnetic data can, for instance, i) clearly demonstrate the occurrence of conformational rearrangements, ii) reveal the presence of minor conformational states, sampled only for a short time, iii) indicate the most representative conformations within the conformational ensemble sampled by the molecule, iv) provide an upper limit to the weight of each conformation.
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http://dx.doi.org/10.1016/j.sbi.2023.102595 | DOI Listing |
J Chem Theory Comput
January 2025
Thermodynamics Research Center, National Institute of Standards and Technology, Boulder, Colorado 80305-3337, United States.
Our recently developed approach based on the local coupled-cluster with single, double, and perturbative triple excitation [LCCSD(T)] model gives very efficient means to compute the ideal-gas enthalpies of formation. The expanded uncertainty (95% confidence) of the method is about 3 kJ·mol for medium-sized compounds, comparable to typical experimental measurements. Larger compounds of interest often exhibit many conformations that can significantly differ in intramolecular interactions.
View Article and Find Full Text PDFPolym Chem
August 2024
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
While the conformational ensembles of disordered peptides and peptidomimetics are complex and challenging to characterize, they are a critical component in the paradigm connecting macromolecule sequence, structure, and function. In molecules that do not adopt a single predominant conformation, the conformational ensemble contains rich structural information that, if accessible, can provide a fundamental understanding related to desirable functions such as cell penetration of a therapeutic or the generation of tunable enzyme-mimetic architecture. To address the fundamental challenge of describing broad conformational ensembles, we developed a model system of peptidomimetics comprised of polar glycine and hydrophobic -butylglycine to characterize using a suite of analytical techniques.
View Article and Find Full Text PDFIntrinsically disordered proteins or regions (IDPs or IDRs) exist as ensembles of conformations in the monomeric state and can adopt diverse binding modes, making their experimental and computational characterization challenging. Here, we developed Disobind, a deep-learning method that predicts inter-protein contact maps and interface residues for an IDR and a partner protein, leveraging sequence embeddings from a protein language model. Several current methods, in contrast, provide partner-independent predictions, require the structure of either protein, and/or are limited by the MSA quality.
View Article and Find Full Text PDFHuman Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. A critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies are in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high throughput structure-based computational screening using ensemble docking for small molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein.
View Article and Find Full Text PDFCellular chromatin displays heterogeneous structure and dynamics, properties that control diverse nuclear processes. Models invoke phase separation of conformational ensembles of chromatin fibers as a mechanism regulating chromatin organization . Here we combine biochemistry and molecular dynamics simulations to examine, at single base-pair resolution, how nucleosome spacing controls chromatin phase separation.
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