Martini 3 protein models - a practical introduction to different structure bias models and their comparison

Abstract

Biophysical characterization of protein structure and dynamics is essential in many scientific fields, including molecular biology, drug discovery, and enzyme design. Molecular dynamics (MD) simulations have become an increasingly important tool for studying these properties. This chapter provides a hands-on introduction to protein modeling with the Martini 3 coarse-grained (CG) force field. We outline its two-layer framework, where the first layer defines molecular topology and interactions, while the second layer applies structural bias to maintain secondary, tertiary, and quaternary structures. Three structure bias approaches - Elastic Network (EN), G[o]Martini, and OLIVES - are discussed, highlighting their advantages and trade-offs. Using a protein kinase as a case study, we demonstrate the step-by-step setup of Martini 3 protein models for simulations with the program package GROMACS, including system preparation, fine-tuning, and validation against atomistic reference simulations. Additionally, we explore the combination of an intrinsically disordered region (IDR) with a structured protein domain. By the end of this chapter, readers will have the necessary expertise to apply Martini 3-based protein modeling to a wide range of research applications.