Enabling Molecular Simulations of Proteins with Lipid Anchors

Many protein molecules that physically associate with cellular membranes have lipid anchors attached to one or more amino acid residues. The 16-carbon palmitoyl lipid tail is often used as an anchor. It is added to proteins by post-translational modification, in a process called “palmitoylation.” Inclusion of the lipid anchor in molecular simulations is crucial for accuracy. Not only does the lipid anchor strengthen the protein’s interaction with the membrane, but its presence may affect the orientation and structural conformation of the protein. The exclusion of these anchors can cause artifacts or misunderstandings of protein function in atomistic simulation. Here, we report a successful effort to determine the partial point charges needed as parameters for atomistic molecular dynamics simulations of caveolin-1, a protein anchored to the membrane by several palmitoyl tails. We have extended a general, modular protocol used to prepare parameters for amino acids, lipids, and other biomolecules through the use of fixed-point charges and terminal capping strategies. Our strategy was tested by parameterizing a palmitoylated cysteine residue for simulation on a protein with three palmitoylation sites. The approach we have used can be further extended to calculate charge parameters for other lipid-linked molecules, including various lipid anchors and drug-lipid conjugates.