A tertiary network couples hydrophobic substitutions to terminal contacts in an IDP
- 1Center for Computational and Integrative Biology
- 2Rutgers University-Camden
- 3Department of Physics
Abstract
Conformational ensembles of intrinsically disordered proteins (IDPs) are sensitive to changes in amino acid sequence. Even chemically conservative substitutions can alter global properties and interactions far from the mutation site, but how these effects propagate across the sequence remains unclear. Here, we investigated six chemically conservative substitutions at site 66, in addition to the naturally occurring Val66 sequence of the intrinsically disordered Brain-Derived Neurotrophic Factor (BDNF) prodomain to understand how a substitution near the center of the sequence affects the termini. Using 896 µs of all-atom explicit-solvent enhanced molecular dynamics simulations and Blobulation, we find that each substitution affects ensemble compactness, which was reflected in contacts between the terminal hydrophobic blobs. For five of the seven sequences, we identified contact associations consistent with an indirect pathway connecting the mutation site to the termini through an intermediate hydrophobic blob. Our findings provide a mechanistic framework for understanding how chemically conservative substitutions produce sequence-dependent changes in IDP ensembles and establish an approach for identifying direct and indirect interaction pathways through which the effects of a mutation propagate.
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BibTeX
@misc{riggs2026tertiary,
title = {{A tertiary network couples hydrophobic substitutions to terminal contacts in an IDP}},
author = {Lindsey M. Riggs and Ruchi Lohia and Grace Brannigan},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008851/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008851/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A tertiary network couples hydrophobic substitutions to terminal contacts in an IDP
AU - Lindsey M. Riggs
AU - Ruchi Lohia
AU - Grace Brannigan
PY - 2026
DA - 2026/09/15
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008851/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008851/v1
AB - Conformational ensembles of intrinsically disordered proteins (IDPs) are sensitive to changes in amino acid sequence. Even chemically conservative substitutions can alter global properties and interactions far from the mutation site, but how these effects propagate across the sequence remains unclear. Here, we investigated six chemically conservative substitutions at site 66, in addition to the naturally occurring Val66 sequence of the intrinsically disordered Brain-Derived Neurotrophic Factor (BDNF) prodomain to understand how a substitution near the center of the sequence affects the termini. Using 896 µs of all-atom explicit-solvent enhanced molecular dynamics simulations and Blobulation, we find that each substitution affects ensemble compactness, which was reflected in contacts between the terminal hydrophobic blobs. For five of the seven sequences, we identified contact associations consistent with an indirect pathway connecting the mutation site to the termini through an intermediate hydrophobic blob. Our findings provide a mechanistic framework for understanding how chemically conservative substitutions produce sequence-dependent changes in IDP ensembles and establish an approach for identifying direct and indirect interaction pathways through which the effects of a mutation propagate.
ER -