skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1352210
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America; Journal Volume: 114; Journal Issue: 9
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Gates, Zachary P., Baxa, Michael C., Yu, Wookyung, Riback, Joshua A., Li, Hui, Roux, Benoît, Kent, Stephen B. H., and Sosnick, Tobin R. Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core. United States: N. p., 2017. Web. doi:10.1073/pnas.1609579114.
Gates, Zachary P., Baxa, Michael C., Yu, Wookyung, Riback, Joshua A., Li, Hui, Roux, Benoît, Kent, Stephen B. H., & Sosnick, Tobin R. Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core. United States. doi:10.1073/pnas.1609579114.
Gates, Zachary P., Baxa, Michael C., Yu, Wookyung, Riback, Joshua A., Li, Hui, Roux, Benoît, Kent, Stephen B. H., and Sosnick, Tobin R. Mon . "Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core". United States. doi:10.1073/pnas.1609579114.
@article{osti_1352210,
title = {Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core},
author = {Gates, Zachary P. and Baxa, Michael C. and Yu, Wookyung and Riback, Joshua A. and Li, Hui and Roux, Benoît and Kent, Stephen B. H. and Sosnick, Tobin R.},
abstractNote = {},
doi = {10.1073/pnas.1609579114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 9,
volume = 114,
place = {United States},
year = {Mon Feb 13 00:00:00 EST 2017},
month = {Mon Feb 13 00:00:00 EST 2017}
}
  • Protein design tests our understanding of protein stability and structure. Successful design methods should allow the exploration of sequence space not found in nature. However, when redesigning naturally occurring protein structures, most fixed backbone design algorithms return amino acid sequences that share strong sequence identity with wild-type sequences, especially in the protein core. This behavior places a restriction on functional space that can be explored and is not consistent with observations from nature, where sequences of low identity have similar structures. Here, we allow backbone flexibility during design to mutate every position in the core (38 residues) of a four-helixmore » bundle protein. Only small perturbations to the backbone, 12 {angstrom}, were needed to entirely mutate the core. The redesigned protein, DRNN, is exceptionally stable (melting point >140C). An NMR and X-ray crystal structure show that the side chains and backbone were accurately modeled (all-atom RMSD = 1.3 {angstrom}).« less
  • An information theory model of hydrophobic effects is used to construct a molecular explanation why hydrophobic solvation entropies of protein unfolding measured by high sensitivity calorimetry converge to zero at a common convergence temperature. The entropy convergence follows directly from the weak temperature dependence of occupancy fluctuations {l_angle}{delta}{ital n}{sup 2}{r_angle} for molecular-scale volumes in water. The macroscopic expression of the contrasting entropic behavior of water relative to common organic solvents is the {ital relative} temperature insensitivity of the water isothermal compressibility compared to hydrocarbon liquids. The information theory model used provides a quantitative description of small molecule hydration and, inmore » addition, predicts that the value of the entropy at convergence is slightly {ital negative}. Interpretations of entropic contributions to protein folding should account for this result. {copyright} {ital 1996 The American Physical Society.}« less
  • The Lum-Chandler-Weeks theory of hydrophobicity [J. Phys. Chem. 103, 4570 (1999)] is applied to treat the temperature dependence of hydrophobic solvation in water. The application illustrates how the temperature dependence for hydrophobic surfaces extending less than 1nm differs significantly from that for surfaces extending more than 1nm. The latter is the result of water depletion, a collective effect, that appears at length scales of 1nm and larger. Due to the contrasting behaviors at small and large length scales, hydrophobicity by itself can explain the variable behavior of protein folding.
  • The study of associations between two biomolecules is the key to understand molecular recognition and function. Molecular function is often thought to be determined by the underlying structures. Here, combining single molecule study of protein binding with an energy landscape inspired microscopic model, we found strong evidences that bio-molecular recognition is determined by flexibilities in addition to structures. Our model is based on coarse grained molecular dynamics performed on the residue level with the energy function biased towards the native binding structure (Go model). With our model, the underlying free energy landscape of the binding can be explored. Two distinctmore » conformational states as free energy minimum, one with partially folding of CBD and significant binding of CBD to CDC42, and another with native folding of CBD and native binding of CBD to CDC42, are clearly seen. This shows the binding process proceeds with significant interface binding of CBD with CDC42 first without complete folding of CBD. Finally binding and folding are coupled with each other cooperatively to reach the native binding state. The single molecule experimental finding of the dynamic fluctuations between the loosely bound and closely bound conformational states can be identified with theoretically calculated free energy minimum and quantitatively explained in our model as a result of binding associated with large conformational changes. Theoretical predictions have identified certain key residues for binding which are consistent with mutational experiments. The combined study provides a test ground for fundamental mechanisms as well as insights into design and further explorations on biomolecular recognition with large conformational changes.« less
  • The authors have isolated a human cDNA that is expressed in the intermediate and late stages of T-cell differentiation. The cDNA encodes a highly hydrophobic protein, termed MAL, that lacks a hydrophobic leader peptide sequence and contains four potential transmembrane domains separated by short hydrophilic segments. The predicted configuration of the MAL protein resembles the structure of integral proteins that form pores or channels in the plasma membrane and that are believed to act as transporters of water-soluble molecules and ions across the lipid bilayer. The presence of MAL and mRNA in a panel of T-cell lines that express bothmore » the T-cell receptor and the T11 antigen suggests that MAL may be involved in membrane signaling in T cells activated via either T11 or T-cell receptor pathways.« less