The pathogenicity, structural and functional exploration of human HMGB1 single nucleotide polymorphisms using in silico study

The human HMGB1 gene mutations have a major impact on several immune-related diseases and cancer. The detrimental effect of non-synonymous mutations of HMGB1 has not been investigated yet, hence the present study aims to examine single nucleotide polymorphisms and their implications on the structure-function of human HMGB1. The multifaceted HMGB1 protein acts as pleiotropic cytokine and regulates essential genes for coordinated cellular functions. The mutational effect on HMGB1 was analyzed by sequence-based homology methods, supervised learning methods, and structure-based methods. The study identified 58 non-synonymous mutations in human HMGB1, out of which only 2 mutations; R10T (rs61742222) and F103C (rs61733675) were classified as the SNPs with highest deleterious and disease-causing mutants. The effect of these mutations in structure of HMGB1 was scrutinized and the R10T mutant found to have a distinct structural behaviour in the B-box domain. In addition, R10T mutant predicted that it affects the MoRF function of HMGB1 and it could disrupt the DNA binding or/and protein partner interaction activity by HMGB1. F103C mutation takes place at the TLR binding and cytokine inducing region of HMGB1, hence it could affect the protein binding activity which involves in many cellular signaling. The study identified potent mutations R10T (a cancer-causing somatic mutation) and F103C (a novel mutation) and these mutations either directly or indirectly hinder DNA binding activity and TLR and cytokine binding of HMGB1. These findings will help in understanding the molecular basis of these promising mutations and functional role of human HMGB1 in cancer and immunological diseases.

AbbreviationsAGER

Advanced glycosylation end product-specific receptor

CXCL

Chemokine (C-X-C motif) ligand

dbSNP

The single nucleotide polymorphism database

HMGB1

High mobility group box 1

LINCS

LINear Constraint Solver

MDS

Molecular dynamics simulation

MoRF

Molecular recognition features

NPT

Number of particle, Pressure and Temperature

NVT

Number of particle, Volume and Temperature

nsSNP

Non-synonymous SNP

PBC

Partial boundary condition

PCA

Principal component analysis

PME

Partial mesh Ewald

RMSD

Root mean square deviation

RMSF

Root mean square fluctuation

SNP

Single nucleotide polymorphism

SPC

Single-point charge

TLR

Toll-like receptor

UTR

Un-translated Region

Advanced glycosylation end product-specific receptor

Chemokine (C-X-C motif) ligand

The single nucleotide polymorphism database

High mobility group box 1

LINear Constraint Solver

Molecular dynamics simulation

Molecular recognition features

Number of particle, Pressure and Temperature

Number of particle, Volume and Temperature

Non-synonymous SNP

Partial boundary condition

Principal component analysis

Partial mesh Ewald

Root mean square deviation

Root mean square fluctuation

Single nucleotide polymorphism

Single-point charge

Toll-like receptor

Un-translated Region

Communicated by Ramaswamy H. Sarma