The research of Charles R. Watts, M.D., Ph.D., focuses on the use of computational chemistry — specifically molecular dynamics — to determine the biophysical properties of proteins and peptides in solution. An understanding of a peptide or protein's solution conformation and dynamics will help in the design of novel therapeutic agents.
The human proteome may contain more than one million inherently disordered peptide or protein motifs and may outnumber those that undergo traditional folding pathways. Many of these are important signals in cellular pathways and some (amyloid beta, alpha-synuclein and tau) play a role in neurological degenerative diseases. The inherent disorder of these systems makes computational techniques more important since the conformational space cannot be accurately determined by solution nuclear magnetic resonance (NMR) spectroscopy, x-ray crystallography or circular dichroism.
- Amyloid Beta. Belonging to the class of inherently disordered peptides, Amyloid Beta's solubility, distribution and biophysical properties within the central nervous system most likely play a complex role in the development of both Alzheimer's dementia and cerebral amyloid angiopathy. Although amyloid fibrils have classically been understood to cause cell death, recent findings have demonstrated that aggregates (dimers, tetramers and octamers) and pre-fibril forms are more cytotoxic than the fibrils themselves.
- Chlorotoxin. Dr. Watts is the primary investigator in a collaborative investigation of Chlorotoxin with Sándor Lovas, Ph.D., of Creighton University School of Medicine. Chlorotoxin is a 36 amino acid peptide found in the venom of the deathstalker scorpion (Leiurus quinquestriatus) with selectivity for slow chloride channels. The peptide has significant sequence homology to other insectotoxins and the inhibitor cysteine knot class of peptides. Chlorotoxin has been demonstrated to bind in a selective fashion to glioma cells and inhibit localized spread of the tumor in adjacent brain tissue. Dr. Watts is performing computational studies to understand the evolutionarily conserved homology of these peptides and to guide the synthesis of more-potent analogs for therapeutic trials.
Significance to patient care
Current therapies for Alzheimer's dementia and Cerebral Amyloid Angiopathy focus on symptom relief, patient safety and palliation. Likewise, treatment of intrinsic brain tumors has been essentially palliative with surgery, radiation and chemotherapy extending life but not providing a cure. The development of novel therapeutic agents provides hope for improving the quality and longevity of patient's lives.
- Member, Adult Advanced Knowledge Assessment Committee, Society of Critical Care Medicine, 2015-present
- Member, Adult Board Review Item Writing Committee, Society of Critical Care Medicine, 2015-present
- Champion of Care, Fairview Foundation, 2014