Title
The acidic tail of HMGB1 regulates its secondary structure and conformational flexibility: A circular dichroism and molecular dynamics simulation study
Author
Wresti L. Anggayasti
Year
2020
Journal
Computational and Structural Biotechnology
Abstract
High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule that
triggers the progression of several pro-inflammatory diseases such as diabetes, Alzheimer’s disease
and cancer, by inducing signals upon interaction with the receptors such as the receptor for advanced glycation
end-products (RAGE) and toll-like receptors (TLRs). The acidic C-terminal tail of HMGB1 is an
intrinsically disordered region of the protein which is known to determine the interaction of HMGB1
to DNA and histones. This study characterizes its structural properties using a combination of circular
dichroism (CD) and molecular dynamics (MD) simulations. The full-length and tail-less forms of
HMGB1 were compared to rationalise the role of the acidic tail in maintaining the stability of the entire
structure of HMGB1 in atomistic detail. Consistent with experimental data, the acidic tail was predicted
to adopt an extended conformation that allows it to make a range of hydrogen-bonding and electrostatic
interactions with the box-like domains that stabilize the overall structure of HMGB1. Absence of the
acidic tail was predicted to increase structural fluctuations of all amino acids, leading to changes in secondary
structure from a-helical to more hydrophilic turns along with increased exposure of multiple
amino acids to the surrounding solvent. These structural changes reveal the intrinsic conformational
dynamics of HMGB1 that are likely to affect the accessibility of its receptors.
2020 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and
Structural Biotechnology. This is an open access article under the CC BY-NC-ND license
Instrument
J-815
Keywords
secondary structure, protein,