Exploring Free Energies of Specific Protein Conformations Using the Martini Force Field

Coarse-grained (CG) level molecular dynamics simulations
are routinely
used to study various biomolecular processes. The Martini force field
is currently the most widely adopted parameter set for such simulations.
The functional form of this and several other CG force fields enforces
secondary protein structure support by employing a variety of harmonic
potentials or restraints that favor the protein’s native conformation.
We propose a straightforward method to calculate the energetic consequences
of transitions between predefined conformational states in systems
in which multiple factors can affect protein conformational equilibria.
This method is designed for use within the Martini force field and
involves imposing conformational transitions by linking a Martini-inherent
elastic network to the coupling parameter λ. We demonstrate
the applicability of our method using the example of five biomolecular
systems that undergo experimentally characterized conformational transitions
between well-defined structures (Staphylococcal nuclease,
C-terminal segment of surfactant protein B, LAH4 peptide, and β2-adrenergic receptor) as well as between folded and unfolded
states (GCN4 leucine zipper protein). The results show that the relative
free energy changes associated with protein conformational transitions,
which are affected by various factors, such as pH, mutations, solvent,
and lipid membrane composition, are correctly reproduced. The proposed
method may be a valuable tool for understanding how different conditions
and modifications affect conformational equilibria in proteins.