Orthogonal Space Tempering Scheme and Its Application to Complex Biomolecular Processes

Molecular dynamics (MD) simulations have advanced greatly in the recent decades, but are not without their limitations. This work first details the pitfalls of MD simulations, then presents the details of a new, robust method, orthogonal space tempering (OST) which can achieve accurate and efficient sampling in MD simulations as well as accurate recovery of desired thermodynamic quantities. This method is then applied to understanding the mechanistic details and free energy of passive transmembrane permeation of small molecules through a lipid bilayer, as well as bulky and charged species. Furthermore, the method is applied to the study of the conformational and dynamical properties of a very important human neuropeptide Y homologue, avian pancreatic peptide.