The forces driving conformational change of proteins and nucleic acids in aqueous solution and proteins in lipid membranes remain incompletely characterized. Theoretical methods are well suited to establishing relationships between structure and energetics, providing critical information for determining the forces underlying biological processes in different cellular microenvironments. Our laboratory uses molecular dynamics (MD) simulations with the recently developed Drude polarizable force field to investigate the conformational ensembles of model peptides and proteins, nucleic acids, and lipid membranes. In this application, we propose a research program that breaks new ground in exploring (1) the forces driving the unfolding of amyloidogenic peptides with and without post-translational modifications, (2) the effects of ions and noncanonical interactions in stabilizing DNA G-quadruplexes (GQ), and (3) the role of induced electronic polarization on small-molecule partitioning and peptide folding in phospholipid membranes. The unifying theme of these projects is an examination of the atomistic details driving conformational change with specific emphasis on the role of induced electronic polarization. During the project period, we propose to investigate conformational ensembles of several amyloidogenic peptides to understand the role of induced electronic polarization on peptide-peptide and peptide- water interactions (hydrogen bonding, electrostatic clashes, and other induced dipole-dipole interactions). Similarly, we will investigate DNA GQ with different folds (parallel, antiparallel, and mixed) to characterize how their nucleobase properties (alignment, dipole moments, etc.) and loop conformational ensembles are impacted by different monovalent ions and noncanonical base-base and base-phosphate interactions that stabilize GQ. The final project comprises simulations of peptides and small molecules in lipid membranes to understand partitioning, thermodynamics, and the strength of hydrogen bonds and other intrapeptide and intermolecular interactions in the hydrophobic core of the membrane, as these interactions are tied to the polarity of the surrounding medium. The specific goals for the five-year project period are to (1) determine interactions among amino acids in amyloidogenic peptides that dictate conformational change, (2) characterize the relative contributions of ions, water, and noncanonical base interactions in stabilizing DNA GQ, and (3) quantify the free energy changes associated with peptide folding and small-molecule partitioning in membranes. These projects are representative of the overall vision of the research program, to apply rigorous theoretical methods to complex biomolecules to understand the molecular basis for a variety of diseases (including neurodegenerative disorders and several types of cancer) and to use the resulting information to carry out computer-aided drug design against new biomolecular targets with the most advanced simulation models currently available.
A complete understanding of the forces driving biomolecular folding and unfolding remain elusive, and delineating these forces is well suited to theoretical investigation. By applying a new, polarizable force field model to systems of amyloid proteins, DNA G-quadruplexes, and lipid membranes, we will determine the role of polarizable electrostatic interactions in these processes. Such information is critical for elucidating the atomic details of many human diseases and potential therapeutic targets.