Prediction of Peptide Binding to Major Histocompatibility II Receptors with Molecular Mechanics and Semi-Empirical Quantum Mechanics Methods

Methods for prediction of the binding of peptides to major histocompatibility complex (MHC) II receptors are examined, using literature values of IC50 as a benchmark. Two sets of IC50 data for closely structurally related peptides based on hen egg lysozyme (HEL) and myelin basic protein (MBP) are reported first. This shows that methods based on both molecular mechanics and semi-empirical quantum mechanics can predict binding with good-to-reasonable accuracy, as long as a suitable method for estimation of solvation effects is included. A more diverse set of 22 peptides bound to HLA-DR1 provides a tougher test of such methods, especially since no crystal structure is available for these peptide-MHC complexes. We therefore use sequence based methods such as SYFPEITHI and SVMHC to generate possible binding poses, using a consensus approach to determine the most likely anchor residues, which are then mapped onto the crystal structure of an unrelated peptide bound to the same receptor. This analysis shows that the MM/GBVI method performs particularly well, as does the AMBER94 forcefield with Born solvation model. Indeed, MM/GBVI can be used as an alternative to sequence based methods in generating binding poses, leading to still better accuracy

Molecular dynamics modelling of skin and hair proteins

The binding free energy is one of the most important and desired thermodynamic properties in simulations of biological systems. The propensity of small molecules binding to macromolecules of human bio-substrates regulates their sub-cellular disposition. This subject is fundamental in transdermal permeation and hair absorption of cosmetic actives. Biomechanical and biophysical properties of hair and skin are related to keratin as their major constituent. A key challenge lies in predicting molecular and thermodynamic basis as the result of small molecules interacting with alpha helical keratin at the molecular level. In addition, elastic properties of human skin which are directly related to the interactions of keratin intermediate filaments remain a challenging subject. Molecular dynamics (MD) simulations provide a possibility of observing biological processes within atomistic resolution providing more detailed insight into experimental results. However, MD simulations are limited in terms of the achievable time scales. Hence, in this thesis MD simulations were employed in order to provide better understanding of the experimental results conducted in parallel and to overcome the main limiting factor of MD – the simulation time. For this purpose, thermodynamic and detailed structural basis have been delivered for small molecules interacting with keratin explaining and validating experimental data. On the top of this the fast free energy prediction tool has been built within all-atom force field by a use of steered molecular dynamics alone. Within the coarse grain approach, the force field was developed for the application of elastic properties of human skin enabling orders of magnitude faster than all-atom force fields simulations. The application of the coarser representation enabled assessing the influence of the natural moisturizing factor composed of small molecules on the elastic properties of the outermost human skin layer. In this work, MD results reached excellent agreement with the experimental data.Open Acces