Addition of side chain interactions to modified Lifson‐Roig helix‐coil theory: Application to energetics of Phenylalanine‐Methionine interactions

Abstract

We introduce here i, i + 3 and i, i + 4 side chain interactions into the modified Lifson-Roig helix-coil theory of Doig et al. (1994, Biochemistry 33:3396-3403). The helixkoil equilibrium is a function of initiation, propagation, capping, and side chain interaction parameters. If each of these parameters is known, the helix content of any isolated peptide can be predicted. The model considers every possible conformation of a peptide, is not limited to peptides with only a single helical segment, and has physically meaningful parameters. We apply the theory to measure the i, i + 4 interaction energies between Phe and Met side chains. Peptides with these residues spaced i, i + 4 are significantly more helical than controls where they are spaced i, i + 5 . Application of the model yields A G for the Phe-Met orientation to be -0.75 kcal.mol", whereas that for the Met-Phe orientation is -0.54 kcal.mol-'. These orientational preferences can be explained, in part, by rotamer preferences for the interacting side chains. We place Phe-Met i , i + 4 at the N-terminus, the C-terminus, and in the center of the host peptide. The model quantitatively predicts the observed helix contents using a single parameter for the side chain-side chain interaction energy. This result indicates that the model works well even when the interaction is at different locations in the helix.

Addition of side‐chain interactions to 310‐helix/coil and α‐helix/310‐helix/coil theory

“…The implementation of this condition would require the consideration of whether each $ or 4 has helix or coil values, rather than each residue. This would be a large increase in complexity, which we do not believe is justified, as our previous model for side-chain interactions in a-helices that used the simpler rule (Stapley et al, 1995) agreed well with experimental data (Stapley et al, 1995;. In each helical stretch, therefore, one residue in the h, conformation is a helix initiating unit and is assigned statistical weight v,.…”

“…Side-chain interactions have been added here to our pure 3,"-helix model in a similar way to the addition of side-chain interactions to the Lifson-Roig a-helix model (Stapley et al, 1995). In a 3,"-helix the side chains are spaced evenly with 120" between successive side chains around the cylinder of the helix.…”

“…For example, if all the Slo-helix parameters w,, v,, n,, c,, p 2 , t,, and tc are set to one, we have the a-helix/coil model with side-chain interactions (Stapley et al, 1995). If, in addition, p2 and q are set to one, we have the a-helix/ coil model with capping (Doig et al, 1994).…”

“…To interpret experiments on helical peptides and make predictions on helices, it is therefore essential to use a helix/coil theory that considers every possible conformation of the peptide and which includes every possible interaction in the peptide that can affect the stability of any helix. We have previously extended the LifsonRoig helix/coil model to include N-and C-capping in the a-helix (Doig et al, 1994) and side-chain interactions in the a-helix (Stapley et al, 1995). Motivated by the growing evidence implicating the importance of the 3,"-helix in peptide and protein folding, we have previously devised models for the 310-helix/coil equilibrium and the 3lo-helix/a-helix/coil equilibrium (Rohl & Doig, 1996).…”

“…Side-chain interactions have been added to this model as follows: pure a-helical regions are treated in exactly the same way as previously described (Stapley et al, 1995). Helical residues in the center of an h,h,h,h,h, quintet given a statistical weight of w, * p I , where p1 is the statistical weight of an i, i + 4 side-chain interaction and -RT lnpl the free energy of the sidechain interaction.…”