Rachael Mansbach
Assistant Professor
Email: re.mansbach@concordia.ca
Proteins are the building blocks of living things, miniature motors that make all of your cells function. Proteins embedded in cell membranes filter out toxic materials or uptake necessary nutrients. Meanwhile, malfunctioning proteins are responsible for a slew of disorders, including Alzheimer’s, type II diabetes and Parkinson’s. Our group works on understanding and designing small molecules and peptides for therapeutic applications such as finding new analgesics for treatment of chronic pain disorders or correcting dysregulation of proteins that lead to Alzheimer’s.
My primary scientific interests lie in designing small molecules and peptides (short proteins) for therapeutic applications: killing bacteria and drugging human cells in beneficial ways — for example to find new analgesics for treatment of chronic pain disorders, or to correct dysregulation of pathways involving the intrinsically disordered proteins that lead to Alzheimer’s. In order to do this, I employ theoretical and computational biophysics tools. I am particularly interested in the burgeoning field of deep learning as applied to molecular dynamics and drug design. Over the past decade, generative deep learning (training an AI to create by pattern-matching to a large amount of data) has demonstrated a fascinating ability to create images and text, and there has been an explosion in the past three years over its application to drug design and molecular dynamics, but it still suffers from lack of interpretability and scalability. As a physicist, I am particularly interested in the interpretability issue.
Current/future projects
With dwindling drug leads and increasing fatalities from multidrug-resistant bacteria, we are teetering on the brink of the post-antibiotic era. New design techniques and approaches for both understanding of antibiotic resistance and design of novel therapeutics are urgently needed. Recently, there has been promising experimental work in the field of antibiotic hybrids, in which sets of different pharmacophores are linked in novel ways, which may lead to molecules with enhanced efficacy or even entirely novel properties.
Although design of novel antibiotics is one approach to combat the growing problem of multidrug resistance, it is unlikely to be sufficient on its own and a multipronged approach is warranted. Another promising line of research for novel drugs with antimicrobial action is the design of peptides with antimicrobial properties that preferentially disrupt the membranes of bacterial cells while displaying a lower affinity for mammalian cells. This is still an active area of research, with only a few candidate peptides having reached clinical trials, due to the continued existence of unwanted side effects such as serum binding or the requirement of potentially-toxic concentrations to be effective.
Owing to their high specificity and binding affinity for various receptors involved in different biological pathways, toxins have for a long time been considered a rich natural source of therapeutic leads. A large and intriguing class of toxins is those that are short, cysteine-rich peptides whose structures are largely controlled by the multiple disulfide bonds that form between the cysteines. Historically, one difficulty in assessing the structure and hence the proposed mechanisms of such toxins has been that it can prove difficult to controllably fold them to their native stable states in vitro. Indeed, there is evidence that certain toxins exist even in vivo in metastable states that are nonetheless potent and in certain cases the “non-native” fold demonstrates higher selectivity and binding affinity which leads to the question of whether we can control these metastable states through sequence, environment or kinetic engineering.
I am looking for a student interested in either polymer theory or molecular dynamics, to explore ways to bring together constrained polymer theories with bond-breaking force field models to map out the free energy landscapes of disulfide-rich toxins.
Rachael Mansbach
Assistant Professor
Email: re.mansbach@concordia.ca
Gnana Gnanakaran
Los Alamos National Lab
Helen Zgurskaya
University of Oklahoma (Center for Antibiotic Discovery and Resistance)
Nick Hengartner
Los Alamos National Lab
Cesar Lopez
Los Alamos National Lab
Srirupa Chakraborty
Los Alamos National Lab
Timothy Travers
Los Alamos National Lab and Pebble Labs
Natalya Watson
MSc student
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