Insight into Post-Translational Protein Modifications through Large-Scale and Long-Scale Molecular Dynamics Simulations

Basic Project Information

Project Title: Insight into Post-Translational Protein Modifications through Large-Scale and Long-Scale Molecular Dynamics Simulations
Implementing Institution: National Science Centre
Funding Program: SONATA
Project Number: UMO-2023/51/D/ST4/02288
Project Duration: 11.07.2024 - 11.07.2027
Total Project Cost: 701,927.00 PLN

Project Description

The goal of this proposed project is to investigate post-translational modifications (PTMs) of proteins. The results of this research will enable the study of biological phenomena related to proteins, in which PTMs are almost always involved, such as regulation of enzyme activity and modification of protein stability. PTMs are complex and fundamental mechanisms of cellular regulation, connected with nearly all known cellular pathways and disease processes. PTMs consist of covalent modifications of amino acid side chains or the C- or N-terminus of proteins, thereby altering their properties and dynamics. Moreover, depending on the biological purpose of a given modification, PTMs may be reversible or irreversible. PTMs occur after protein synthesis and may require the presence of enzymes or occur spontaneously.

PTMs play a crucial role in almost all biological processes and numerous molecular functions. Therefore, the effects of dysfunctional PTMs can be observed in many diseases, such as neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease), heart failure, autoimmune diseases, and cancers. There are over 400 types of PTMs. Some seem very specific and so far have been found only in a few protein types, such as polyglycylation, polyglutamylation, and tyrosination/detyrosination (commonly at the C-terminus of tubulin).

Unfortunately, detailed analysis and characterization of PTMs using experimental methods pose serious challenges, mainly due to the unstable and transient nature of many of these modifications. Although significant progress has been made in PTM research over recent decades, both experimental and theoretical approaches still face difficulties in effectively analyzing their structural and dynamic impacts on protein function and molecular mechanisms.

This project aims to answer the question: How do PTMs affect protein structure and function? To that end, the coarse-grained UNRES force field will be extended with new interaction sites for PTMs, enabling innovative research in this key area of PTM study.