Determining the effects of local sequence on Met-Met interactions in Intrinsically Disordered Proteins
While many proteins fold and have well-defined structures, many other proteins (and parts of proteins) do not. These are konwn as Intrinsically Disordered Proteins (IDPs). In the absence of tertiary structure, it is a major challenge to identify residue-residue interactions and overall confromational trends. This project involves using genomic data and simulations to elucidate patterns involving both of these in IDPs. Our lab developed the blobulator, an amino acid sequence-based edge detection tool - which can be found here.
Computing absolute binding affinities by Streamlined Alchemical Free Energy Perturbation
Not all cell membranes are identical; they’re made up of a wide range of lipids which can affect critical cell functions like metabolism or nerve signaling. We are trying to answer the question of “What is the probability that lipid X affects the function of membrane protein Y?” We get at that question by computing free energies of binding affinities using the SAFEP framework. In this framework we use molecular dynamics simulations to compare the bound and unbound states of the lipid and protein. Here we see a lipid specifically and tightly bound to the Erwinia ligand gated ion channel, a model for a large family of neuronal proteins, modulating the protein's activity. From our MD simulations, we can determine the probabilities of binding and so compare the effects of different lipids.
Asymmetric Membrane Curvature in SARS-CoV-2 E protein
When the virus that causes Covid-19 replicates inside your cells, the Envelope protein (E protein) wraps the baby virion in a blanket of your own organellar membrane material. This helps the new virion escape detection by your immune system and allows it to escape its host cell, continuing the Covid-19 infection cycle. It is not known how this small, pentameric protein could induce such extreme curvature in a membrane surface, but that is what my research seeks to uncover. To understand the relationship between E protein and membrane curvature, we developed a toolkit for analysis of membrane disruption by proteins and other inclusions, called nougat. Shown above is a snapshot of the SARS-CoV-2 Envelope (E) protein (grey) bending a 100% POPC membrane (cyan) in coarse-grain molecular dynamics simulation.
The role of membrane composition on the aggregation and stability of nanoparticles
Targeted drug delivery is a rapidly expanding field, with promising technologies to control the spatial-temporal release of drugs. Some of the most promising delivery vehicles are polymer and lipid vesicles hybridized with metallic nanoparticles. Our primary focus is understanding nanoparticle-membrane interactions and molecular mechanisms underlying nanoparticle aggregation and lipid disruption around nanoparticle inclusions. We use molecular dynamics simulations to understand these interactions at the molecular level. Shown above is an image of two aggregated dodecanethiol coated charged nanoparticles in a POPC membrane. Nanoparticles are represented in ochre and cyan, ligands in blue, lipid tails in grey and lipid head groups in green.
Using coarse-grain simulations to identify the role of ceramide in regulating protein folding
Under phosphate starvation, C.crescentus synthesizes a sphingolipid known as ceramide, previously seen only in Sphingomonas species. In Sphingomonas, ceramide is important for the outer membrane integrity. However, the role of ceramide in C.crescentus remains under study. We have recently identified a novel anionic SLs, where the anionic head group is phosphoglycerate. Removing the head group phosphoglycerate induces an unfolded-protein stress response. Our research aims to understand how ceramide regulates the protein folding process. We use coarse-grain systems and molecular dynamics to study these interactions.
Molecular Mechanism of reversed Temperature-dependence of ATP Synthesis in Glacier Ice Worms
F0F1 ATP synthase is a highly conserved enzyme across species, that produces ATP. In a surprising contrast with temperate organisms, glacier ice worms display elevated ATP levels as temperatures decline. The increased energy expenditure is used as a strategy for survival at cold temperatures, but the mechanism is unknown. To investigate the underlying mechanism of elevated ATP levels in glacier ice worms, we are investigating the effects of temperature on the dynamics of the F0 domain (shown above) in glacier ice worms compared to their temperate counterparts. Shown above is the ATP6 extension that is unique to glacier ice worms and is hypothesized to accelerate the flow of protons across the membrane.