Details

Autor(en) / Beteiligte

• Patel, Samarthaben J

Titel

Molecular Simulations to Characterize the Assembly and Transport of Biomolecules in Solution and at Lipid Interfaces

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2021

Link zum Volltext

• ProQuest

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Biomolecules capable of bypassing the cell membrane are of great importance for drug and gene delivery. However, there is a significant challenge in predicting the behavior of these biomolecules in biological environments. In this dissertation, we focus on two major class of biomolecules: 1) small amphiphilic bacterial signals, and 2) membrane proteins/peptides with charged residues in their loops and transmembrane helices. In the first part, we study the amphiphilic behavior of bacterial quorum sensing (QS) signal molecules which are produced by common bacteria to coordinate group behaviors. N-acyl-l-homoserine lactones (AHLs) are commonly used signals that possess a polar homoserine lactone headgroup and a nonpolar aliphatic tail. We use a combination of biophysical characterization and atomistic molecular dynamics (MD) simulations to characterize the self-assembly behaviors of 12 structurally related AHLs, and predict their thermodynamically preferred aggregate structures using alchemical free energy calculations. We then study the large-scale remodeling in model lipid membranes promoted by AHLs, and predict differences in translocation free energies are reflected in both the type and extent of reformation. We then use an implicit solvent model, called COSMOmic, to screen the water-membrane partition and translocation free energies for 50 native and non-native QS modulators at a significantly reduced computational cost compared to atomistic MD simulations. In the second part, we study the translocation of charged moieties of a peptide across a lipid bilayer. The hydrophobic core of the lipid bilayer is considered a barrier to the translocation of charged species. Despite this barrier, some peptides can interconvert between transmembrane and surface-adsorbed states by “flipping” charged flanking loops across the bilayer on a surprisingly rapid second-minute time scale. We utilize all-atom temperature accelerated molecular dynamics (TAMD) simulations to predict the likelihood of loop-flipping without predefining specific loop-flipping pathways in single-transmembrane helix peptides. Along with TAMD, we use the swarms-of-trajectories string method to analyze loop-flipping pathways and free energy barriers across lipid bilayers as a function of multiple collective variables. Overall, our results provide insights into the self-assembly and translocation of biomolecules across lipid bilayers which could prove useful in the design of synthetic drug delivery and sensing agents.