Using a Coarse-Grained Modeling Framework to Identify Oligomeric Motifs with Tunable Secondary Structure

Area of Science:

• Computational chemistry and biophysics
• Molecular modeling and simulation
• Protein structure prediction

Background:

• Coarse-grained (CG) modeling simplifies complex molecular systems by representing groups of atoms as single interaction sites.
• Exploring general theories of molecular behavior independent of specific chemical details is crucial for understanding biological macromolecules.
• Cooperative secondary structures in proteins, such as helices, play vital roles in their overall function and stability.

Purpose of the Study:

• To present cg_openmm, a novel Python-based simulation framework for coarse-grained modeling of hetero-oligomers.
• To enable the screening of these models for structural and thermodynamic characteristics of cooperative secondary structures.
• To facilitate the identification and characterization of stable secondary structures through cooperative folding transitions.

Main Methods:

• Development of a Python framework (cg_openmm) for building coarse-grained topology and initial configurations.
• Utilizing GPU-accelerated replica exchange molecular dynamics (REMD) simulations via the OpenMM software package.
• Employing postprocessing analysis tools including native contact analysis, heat capacity calculations, and free energy of folding computations.

Main Results:

• Demonstration of cg_openmm capabilities using a 1-1 Lennard-Jones coarse-grained model.
• Identification and characterization of force-field parameters leading to stable helix formation via cooperative folding.
• Tuning of helix geometries and stabilities by manipulating coarse-grained force-field parameters.

Conclusions:

• cg_openmm provides a powerful and flexible platform for coarse-grained simulations of protein structures.
• The framework effectively identifies and characterizes cooperative folding transitions leading to stable secondary structures.
• Force-field parameterization at the coarse-grained level offers a viable strategy for designing and controlling protein structural motifs.