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Physicochemical Principles Governing the Intrinsically Disordered Salivary Peptide Histatin 5 : Ensemble Structure, Electrostatics, and Environmental Responsiveness

Svensson, Oskar LU ; Lenton, Samuel and Skepö, Marie LU orcid (2026) In Journal of Physical Chemistry B 130(14). p.3799-3807
Abstract

Histatin 5 (Hst5) is a histidine-rich intrinsically disordered protein (IDP) whose biological function arises from a highly heterogeneous conformational ensemble and environmental sensitivity. Unlike structured antimicrobial peptides that rely on persistent secondary motifs, Hst5 remains disordered across a wide range of conditions, enabling continuous adaptation to changes in pH, ionic strength, metal-ion concentration, macromolecular crowding, and interfaces such as membranes and mineral surfaces. Recent advances in small-angle X-ray scattering (SAXS), neutron-based methods, and surface-sensitive techniques, combined with computer simulations, have allowed quantitative characterization of Hst5′s ensemble structure, thermodynamics, and... (More)

Histatin 5 (Hst5) is a histidine-rich intrinsically disordered protein (IDP) whose biological function arises from a highly heterogeneous conformational ensemble and environmental sensitivity. Unlike structured antimicrobial peptides that rely on persistent secondary motifs, Hst5 remains disordered across a wide range of conditions, enabling continuous adaptation to changes in pH, ionic strength, metal-ion concentration, macromolecular crowding, and interfaces such as membranes and mineral surfaces. Recent advances in small-angle X-ray scattering (SAXS), neutron-based methods, and surface-sensitive techniques, combined with computer simulations, have allowed quantitative characterization of Hst5′s ensemble structure, thermodynamics, and interactions. This work synthesizes current understanding of how intrinsic disorder, charge regulation, histidine chemistry, and multiscale interactions govern Hst5 behavior. Beyond its biological relevance, Hst5 has emerged as a benchmark system for elucidating general physicochemical principles of IDPs and for testing integrative and machine-learning approaches that map sequence features to ensemble architecture.

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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Physical Chemistry B
volume
130
issue
14
pages
9 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:105035464566
  • pmid:41911046
ISSN
1520-6106
DOI
10.1021/acs.jpcb.6c00591
language
English
LU publication?
yes
id
e6d55d1b-ff27-4a01-94a0-a80da3d7eb1a
date added to LUP
2026-06-09 10:01:39
date last changed
2026-06-10 03:00:02
@article{e6d55d1b-ff27-4a01-94a0-a80da3d7eb1a,
  abstract     = {{<p>Histatin 5 (Hst5) is a histidine-rich intrinsically disordered protein (IDP) whose biological function arises from a highly heterogeneous conformational ensemble and environmental sensitivity. Unlike structured antimicrobial peptides that rely on persistent secondary motifs, Hst5 remains disordered across a wide range of conditions, enabling continuous adaptation to changes in pH, ionic strength, metal-ion concentration, macromolecular crowding, and interfaces such as membranes and mineral surfaces. Recent advances in small-angle X-ray scattering (SAXS), neutron-based methods, and surface-sensitive techniques, combined with computer simulations, have allowed quantitative characterization of Hst5′s ensemble structure, thermodynamics, and interactions. This work synthesizes current understanding of how intrinsic disorder, charge regulation, histidine chemistry, and multiscale interactions govern Hst5 behavior. Beyond its biological relevance, Hst5 has emerged as a benchmark system for elucidating general physicochemical principles of IDPs and for testing integrative and machine-learning approaches that map sequence features to ensemble architecture.</p>}},
  author       = {{Svensson, Oskar and Lenton, Samuel and Skepö, Marie}},
  issn         = {{1520-6106}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{14}},
  pages        = {{3799--3807}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Physical Chemistry B}},
  title        = {{Physicochemical Principles Governing the Intrinsically Disordered Salivary Peptide Histatin 5 : Ensemble Structure, Electrostatics, and Environmental Responsiveness}},
  url          = {{http://dx.doi.org/10.1021/acs.jpcb.6c00591}},
  doi          = {{10.1021/acs.jpcb.6c00591}},
  volume       = {{130}},
  year         = {{2026}},
}