Assessment of Molecular Dynamics Force Fields for Studies of Intrinsically Disordered Peptides

The prevalence of Intrinsically Disordered Proteins (IDPs) in the eukaryotic genome, associated with both physiological function and diseases, provides motivation to effectively characterize these systems. Experimental methods can be limited in their ability to characterize IDPs. Molecular dynamics (MD) simulations can provide details of these systems with atomistic detail. However, the performance of MD simulations is always based on approximations and assumptions of some extent. The reliability of MD simulation results largely depends on the correctness and precision of these assumptions. There are known issues in MD regarding the simulation of IDPs and many of the force fields commonly used for MD simulations are not typically validated for many small, unfolded peptides or IDPs. To this end, Chapter 3 assesses multiple state-of-the-art MD force fields in their capacity to produce the intrinsic backbone dynamics, as characterized by Ramachandran distributions, of 14 of the 20 amino acids as the central amino acid resiude of GxG tripeptides with respect to a comprehensive set of experimental data. An additional study was performed for a select tetra- and pentapeptide, GRRG and GRRRG. Generally, MD force fields do not reproduce amino acid-specific conformational properties or nearest neighbor interactions. A model Ramachandran distribution, constructed using a linear combination of Gaussian subdistributions, were shown to produce experimental results better than MD by at least an order of magnitude. Errors of the dynamics of amino acid residues in short peptides likely proliferates in larger IDPs, effectively limiting the effectiveness of MD for studying disease-related IDPs. Chapter 4 extends the assessment of Chapter 3 to protein-protein interactions. First, the effect of mixed solvent of ethanol and water on GAG peptide aggregates, which surpringly form gels in experiments, is investigated. Then, the ability for MD force fields to capture the solubility of a short, natively folded protein is assessed. Finally, based on the analyses throughout the thesis, the potential physiological function of an IDP associated with Alzheimer's Disease is explored via protein-soluble lipid interactions.