Anderson, Jakob Edward, authorRappé, Anthony, advisorMcCullagh, Martin, advisorKennan, Alan, committee memberChen, Eugene, committee memberShipman, Patrick, committee member2022-05-302024-05-242022https://hdl.handle.net/10217/235358Molecular aggregation is largely dictated by noncovalent interactions and is a phenomenon found in a broad list of disciplines. Computational and theoretical methods, such as molecular dynamics simulations and Quantum Mechanical calculations, are well suited techniques to study the noncovalent association of various systems as they provide atomistic resolution and experimentally comparable results for the timescales on which association occurs. The studies found in this dissertation are introduced in the first chapter and are put in the context of using computational methods to study the noncovalent association and aggregation of small molecules. Chapters two, three, and four provide a foundation for the rational design of dipeptides for a given application. A wide range of potential applications for diphenylalanine (FF) have been proposed which would benefit from the development of design principles. Chapter two discusses the complexity of the noncovalent interactions at multiple stages in the FF self-assembly process. Specifically, we suggest the initial aggregation of FF is predominantly driven by electrostatics, and after a reorientation event, nanotube growth is suggested to be driven by solvent mediated forces. The results from this chapter use an array of generalized analyses enabling quantitative comparisons to future dipeptide studies. The impact of sidechain modification for either FF residue is studied in chapter three by considering valine-phenylalanine (VF) and phenylalanine-valine (FV). While the monomeric conformations are shown to sample the same states for these two dipeptides, the probabilities for state sampling as well as the water dynamics around the peptide bond are shown to differ. Chapter four connects chapters two and three by considering both the behavior of sequence dependence and dimerization of VF, FV, isoleucine-phenylalanine, and phenylalanine-isoleucine relative to that of FF. The modification of the C-terminus of FF to a smaller hydrophobic sidechain is hypothesized to enable tighter packing from this study. Additionally, N-terminus FF modification is hypothesized to increase the solvent mediated forces during dimerization in agreement with the results from chapter three. While not a completed study, chapter four provides a foundation for the continued development of design principles for FF-derivatives. A novel approach to computing the free energy of association from Quantum Mechanical calculations is then described in chapter five. Due to the treatment of low energy frequencies as harmonic and a lack of temperature dependence, calculations of the entropy of associating molecules is inaccurate. The rigid-rotor-Gaussian-oscillator approximation proposed addresses these issues by treating low lying modes with anharmonic Gaussian potentials and wave functions as well as adding a temperature dependence to the partitioning between vibrational and translational/rotational modes. This approximation significantly reduces the error in computing the entropy of associating molecules resulting in a more accurate calculation of the total free energy. The results from these studies as well as future studies based on the work in this dissertation are then summarized in the final chapter.born digitaldoctoral dissertationsengdipeptidesmolecular dynamicsassociationquantum mechanicsentropic correctionTextThe material is open access and distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 United States License (https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode).