Insights into Protein Unfolding under pH, Temperature, and Shear using Molecular Dynamics Simulations

TL;DR

This study uses molecular dynamics simulations to reveal that high temperature, acidic pH, and shear stress induce unique unfolding pathways in proteins, informing stabilization strategies for therapeutic protein design.

Contribution

The paper demonstrates that different external stressors cause distinct unfolding mechanisms in proteins, providing detailed structural insights through all-atom simulations.

Findings

High temperature disrupts secondary structures.

Acidic pH causes tertiary structure alterations.

Shear stress leads to tertiary perturbation followed by secondary loss.

Abstract

Protein biologics hold immense potential in therapeutic applications, but their ephemeral nature has hindered their widespread application. The effects of different stressors on protein folding have long been studied, but whether these stressors induce protein unfolding through different pathways remains unclear. In this work, we conduct all-atom molecular dynamics simulations to investigate the unfolding of bovine serum albumin (BSA) under three distinct external stressors: high temperature, acidic pH, and shear stress. Our findings reveal that each stressor induces unique unfolding patterns in BSA, indicating stressor-specific unfolding pathways. Detailed structural analysis showed that high temperature significantly disrupts the protein's secondary structure, while acidic pH causes notable alterations in the tertiary structure, leading to domain separation and an extended shape. Shear stress initially perturbs the tertiary structure, initiating structural rearrangements followed by a loss of secondary structure. These distinct unfolding behaviors suggest that different stabilization strategies are required to enhance protein stability under various denaturation conditions. Insights from these unfolding studies can inform the design of materials, especially polymers, aimed at improving protein stability.