Computer simulations of peptides and peptidomimetics

Conformational preferences of peptides in solution, ranging from small flexible peptidomimetics and their more rigid cyclyzed forms to model peptide systems with regular structures like the α-helix, β-sheet and the triple helix found in proteins, were analyzed using molecular dynamics and free energy simulations. The conformational free energy surfaces of the model peptides were explored using the multidimensional Conformational Free energy Thermodynamic Integration (CFTI) protocol. Structural analysis coupled with the decomposition of the overall free energy differences into contributions from energy and entropy, and different interactions in the studied molecular system provided insights into the microscopic mechanism of the studied processes. Free energy landscapes of the model peptide helices indicated the stabilization of the π-helix and the destabilization of the 3₁₀-helix, relative to the standard α-helix on solvation. The (Ala)₁₀ π-helical structure in solution is markedly different from the generally accepted model and our π-helical structure had strong favorable interactions with the solvent, low internal strain and a volume identical to that of the α-helix, suggesting that π-helices should be considered as possible conformers worthy of further computational and experimental studies. The free energy surfaces of a model β-strand and an antiparallel β-sheet showed the preference for the right-handed twist in β-structures The optimum twist of the sheet was found to be 31° for a two-residue unit and was favored because of low internal strain and favorable overall nonbonded interactions. A preliminary study of three collagen-like model peptide systems using the CFTI method successfully reproduced the experimental structural features of the collagen triple helix indicating that our method and the parameter set could be used to gain insight into collagen's biological properties. Molecular dynamics simulations of a series of peptidomimetics and their cyclic analogues in different solvents help correlate the different conformations adopted by the systems to their physicochemical and biological activities. Water and octane, modeled explicitly, were used as solvents to mimic the change of environment experienced by the solutes upon partition from water to membrane in the trans-cellular transport pathway. The linear forms adopted markedly tent conformations in polar and nonpolar environments while the cyclic forms showed limited response to environmental changes. Based on the structural analysis and the his of the solute-solvent interaction energies, our results predicted a large unfavorable energy change for transferring the linear forms from water to octane and a much less unfavorable energy change for the cyclic forms. This was in agreement with the experimental findings that the linear compounds were not transported via the traps-cellular transport pathway while the cyclic forms exhibited an enhanced passive traps cellular transport. As simulations with explicit solvents are computationally expensive, approximate models based on dielectric continuum, using the Poisson-Boltzmann equation were considered. This model qualitatively reproduced explicit solvent red of the rigid model peptide helices, but did not give reliable results for the more flexible peptidomimetics.