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### A systematic review of high mobility group (HMG) peptides

#### Introduction

High Mobility Group (HMG) proteins are a class of non-histone proteins widely present in the nucleus of eukaryotic cells, named for their fast migration speed in gel electrophoresis. They regulate gene expression, DNA repair and chromatin dynamic structure by interacting with DNA or chromatin. In recent years, the application of HMG peptides (i.e., their functionally active fragments or synthetic analogs) in basic research and biomedicine has attracted much attention. This article systematically classifies HMG peptides and details their structure, physicochemical properties, functions and potential applications.

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### 1. Classification and subfamilies of HMG proteins

HMG proteins are divided into three categories according to their structural characteristics: **HMGA**, **HMGB** and **HMGN**. Each category has a unique structural domain and functional mechanism.

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#### 2. HMGA family: chromatin structure regulators

**1. Subtypes and structures**

- **HMGA1** (including HMGA1a and HMGA1b) and **HMGA2**, composed of about 100 amino acids, contain 3 "AT-hook" domains, and preferentially bind to DNA regions rich in AT base pairs.

**2. Physical and chemical properties**

- **Molecular weight**: about 11-12 kDa.

- **Isoelectric point (pI)**: acidic (pI 4.5-5.5), because it is rich in acidic amino acids (such as aspartic acid).

- **Solubility**: high water solubility, but easy to precipitate under high salt conditions.

- **Color and stability**: the pure product is a colorless lyophilized powder; it is sensitive to proteases and needs to be stored at low temperature (-80°C).

**3. Functions and advantages**

- **Chromatin remodeling**: promotes transcription factor binding by bending DNA.

- **Cancer association**: Overexpressed in a variety of tumors (such as breast cancer and colon cancer), becoming a potential therapeutic target.

- **Advantage**: Small molecular weight enhances cell penetration and is suitable for gene editing vector design.

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#### 3. HMGB family: multifunctional inflammatory mediators

**1. Subtypes and structures**

- **HMGB1**, **HMGB2**, **HMGB3**, contain two HMG-box domains and an acidic C-terminal tail, and the structure is highly conserved.

**2. Physicochemical properties**

- **Molecular weight**: about 25-30 kDa.

- **Isoelectric point**: pI 5.0-6.5, the C-terminal acidic tail contributes negative charge.

- **Solubility**: easily soluble in neutral buffer, the oxidation state (such as disulfide bond formation) affects the conformation and function.

- **Color and oxidation sensitivity**: colorless in the reduced state, aggregation (turbidity) may occur after oxidation.

**3. Functions and advantages**

- **DNA repair**: Promotes the recruitment of damage recognition proteins.

- **Inflammation regulation**: HMGB1 acts as a damage-associated molecular pattern (DAMP) to activate the TLR4/NF-κB pathway.

- **Diagnostic value**: Serum HMGB1 levels are positively correlated with the severity of diseases such as sepsis and rheumatoid arthritis.

- **Therapeutic potential**: Neutralizing antibodies or antagonistic peptides (such as BoxA peptides) can inhibit inflammatory responses.

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#### 4. HMGN family: Chromatin accessibility regulators

**1. Subtypes and structures**

- **HMGN1-5**, containing nuclear localization signals (NLS) and chromatin binding domains, affect chromatin structure by competitively binding to nucleosomes.

**2. Physicochemical properties**

- **Molecular weight**: about 10-15 kDa.

- **Isoelectric point**: pI 7.5-9.0, because it contains more basic amino acids (such as lysine).

- **Solubility**: Low ionic strength buffer (such as Tris-HCl) is required to maintain solubility.

- **Stability**: High temperature resistance (some isoforms are still stable at 60°C), but easily phosphorylated.

**3. Functions and advantages**

- **Enhanced transcription**: Promotes gene expression by increasing the acetylation level of histone H3K14.

- **Stem cell regulation**: HMGN3 is involved in maintaining embryonic stem cell pluripotency.

- **Delivery advantage**: Alkaline properties facilitate complexing with negatively charged nucleic acids (such as siRNA) for use in gene delivery systems.

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### 5. Application prospects of HMG peptides

1. **Cancer treatment**: Antisense oligonucleotides or small molecule inhibitors targeting HMGA1 (such as netropsin analogs) have entered clinical trials.

2. **Anti-inflammatory therapy**: HMGB1 antagonist peptides (such as Acetylated BoxA) significantly alleviate sepsis symptoms in animal models.

3. **Gene editing assistance**: HMGN peptides are combined with CRISPR-Cas9 to improve chromatin targeting efficiency.

4. **Diagnostic marker**: HMGB1 ELISA kits have been used for clinical inflammation monitoring.

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### 6. Summary and Outlook

HMG peptides have shown broad prospects in basic research and translational medicine due to their unique structural plasticity and versatility. In the future, it is necessary to further solve the problems of in vivo stability (such as PEG modification) and targeted delivery to accelerate clinical application. At the same time, exploring the synergistic effects and epigenetic regulatory networks among HMG family members will provide new strategies for precision medicine.