Difference Between Folded and Unfolded Protein

The key difference between folded and unfolded protein is that folded protein is a biologically active structure while unfolded protein is a biologically inactive structure.

Translation produces a linear chain of amino acid sequence which does not possess a stable 3D structure. Therefore, amino acid sequences interact with each other and fold via a complex process called protein folding. It is an important process which makes a protein biologically active. The correct native structure of a protein is very crucial for its function. Polypeptide chains fold to become a biologically active protein in its 3D structure. Folded proteins are held together by various molecular interactions. They have a stable 3D structure; hence, they are biologically active, unlike unfolded proteins.

CONTENTS

1. Overview and Key Difference
2. What is a Folded Protein
3. What is an Unfolded Protein 
4. Similarities Between Folded and Unfolded Protein
5. Side by Side Comparison – Folded vs Unfolded Protein in Tabular Form
6. Summary

What is a Folded Protein?

Folded protein is a biologically active protein which has attained its stable 3D structure. Protein folding is the process which results in folded proteins, and it occurs in the endoplasmic reticulum. Protein folding process is thermodynamically favorable. It occurs as a spontaneous reaction. The first step of the protein folding is the formation of secondary structures such as alpha helices or beta sheets from the primary structure of a protein. Secondary structures then pave the way to tertiary structures. α-helices and β-sheets fold into a three-dimensional structure. Tertiary structures then further fold and form the quaternary structure of a protein.

Several factors influence the ability of proteins to fold into their correct functional forms. Some of the factors are electric and magnetic fields, temperature, pH, chemicals, space limitation and molecular crowding. Incorrect folding can lead to various disease conditions. Alzheimer’s disease and Cystic fibrosis are two common diseases caused by protein misfolding.

During the folding, polypeptide chains interact through covalent and noncovalent interactions. Hydrophobic interactions and van der Waals interactions are two types of noncovalent interactions that help in protein folding. Noncovalent interactions are weak and short-ranged interactions.  However, they provide fundamental driving forces. Covalent interactions such as disulfide bonds and ionic bonds also help in protein folding, and they are strong interactions. Protein folding takes place in an aqueous environment.

What is an Unfolded Protein?

Unfolded protein is a linear amino acid sequence. It exists in the primary structure, which is a polypeptide chain. Unfolded proteins are biologically inactive. Moreover, it is a disordered open structure with loosely packed side chains. In other words, unfolded proteins lack an ordered structure. Unfolded proteins contribute to the pathology of many diseases.

In order to become a functional protein, unfolded proteins must fold into stable three-dimensional conformations. In many cases, multiple polypeptide chains must assemble into a functional complex. In addition to that, most proteins undergo modifications such as cleavage or covalent attachments with carbohydrates and lipids.

What are the Similarities Between Folded and Unfolded Protein?

• Extreme temperature, extreme pH, mechanical forces and chemical denaturants can covert a folded protein into an unfolded protein.
• Denaturation of proteins is a process of transition from the folded to the unfolded state.

What is the Difference Between Folded and Unfolded Protein?

Folded protein is an ordered, globular protein with a tightly packed hydrophobic core while unfolded protein is a disordered, open structure with loosely packed side chains. So, this is the key difference between folded and unfolded protein. Furthermore, the folded proteins are biologically active and function correctly, while the unfolded proteins are biologically inactive and do not function correctly.

Below infographic shows a detailed comparison of both proteins to discern the difference between folded and unfolded protein clearly.

Summary – Folded vs Unfolded Protein

Generally, proteins must be correctly folded into specific, stable, three-dimensional conformations in order to function correctly. Unfolded proteins are biologically inactive while folded proteins are biologically active. Folded proteins have a 3D structure while unfolded proteins are disordered, open structures with loosely packed side chains. Thus, this summarizes the difference between folded and unfolded protein.

Reference:

1. Cooper, Geoffrey M. “Protein Folding and Processing.” The Cell: A Molecular Approach. 2nd Edition., U.S. National Library of Medicine, 1 Jan. 1970, Available here.
2. Cheriyedath, Susha. “Protein Folding.” News, 26 Feb. 2019, Available here.

Image Courtesy:

1. “225 Peptide Bond-01” By OpenStax College – Anatomy & Physiology, Connexions Web site, Jun 19, 2013. (CC BY 3.0) via Commons Wikimedia
2. “Unfolded Protein Response” By Tifol – (CC BY-SA 4.0) via Commons Wikimedia