Marcos Sotomayor received his B.Sc. in Physics from Universidad de Chile in 2001 and his Ph.D. in Physics from the University of Illinois at Urbana-Champaign in 2007. As a graduate student with Dr. Klaus Schulten in the theoretical and computational biophysics group he did molecular dynamics simulations of proteins involved in mechanotransduction. His computational studies predicted the conductance of the ion channel MscS structure, as well as the elasticity of ankyrin and cadherin repeats. After finishing his Ph.D., he joined the laboratories of David P. Corey and Rachelle Gaudet to do experimental work as a postdoctoral researcher at Harvard University. There he solved the first X-ray crystal structure of a heterophilic cadherin complex essential for hearing and balance. During his postdoctoral tenure he was a Howard Hughes Medical Institute fellow of the Helen Hay Whitney foundation. Marcos received a prestigious NIH K99/R00 award and started at OSU in July of 2013. In 2015 he received a Distinguished Undergraduate Research Mentor award from the undergraduate research office at OSU and was selected as an Alfred P. Sloan Research Fellow in Neuroscience.
Mechanotransduction – Cellular Adhesion – Structural Biology – Molecular Dynamics Simulations – Protein Biochemistry and Biophysics
Living organisms rely on macroscopic and microscopic structures that produce and transform force to survive: from cell volume regulation to sound transduction and cellular adhesion, handling of forces is essential to life. Research in the Sotomayor group focuses on elucidating the molecular mechanisms underlying vertebrate mechanosensation and selective cellular adhesion. We use interdisciplinary and quantitative approaches to reveal structure-function relationships in macromolecular complexes such as those found in the mechanotransduction apparatus of inner-ear hair cells and in the cadherin adhesion machinery of epithelial tissues and synapses. Our combined experimental-computational research approach provides a unique structural framework to understand protein mechanics and function in hearing and balance, as well as in tissue morphogenesis, cancer, and neuronal connectivity.
Structural Biology and Simulations of Proteins Involved in Mechanosensation
Mechanical forces produced by sound, gravity, and osmotic pressure are sensed by different organisms through multiple mechanisms that usually involve mechanosensitive ion channels and accessory proteins conveying tension. We are using a combination of X-ray crystallography and computational biology to determine the structure and dynamics of macromolecular complexes involved in vertebrate mechanotransduction. We are particularly interested in structures of cadherins and membrane proteins and ion channels involved in sound perception, as well as in large-scale all-atom molecular dynamics simulations of force transduction.
Force Spectroscopy of Hair-Cell Tip Links
Hair cells are specialized and sensitive mechanoreceptors that transform mechanical stimuli into electrical signals in the inner ear. The tip link bond is essential for hair-cell mechanotransduction but little is known about the forces it can withstand and the molecular mechanisms underlying its noise-induce damage. The discovery of the tip-link molecular components and our resolution of the first X-ray crystallographic structure of part of the bond opened the door to explore the molecular determinants of its strength. We are using single-molecule force spectroscopy experiments and simulations to probe the strength of the tip-link bond and discover molecular mechanisms associated with its formation, rupture and malfunction in deafness.
Molecular Connectomics: Binding Specificity in Novel Cadherin Heterophilic Complexes
Selective cell-cell adhesion is essential for tissue development and formation of complex and structured multicellular organs. Multiple families of cell-adhesion molecules have been identified; the cadherin superfamily of calcium-dependent adhesion proteins is one of the largest and has been implicated in tissue and organ morphogenesis and cancer. We are using bioinformatics tools and high-throughput methodologies to discover novel cadherin heterophilic complexes and reveal the structural determinants of their binding specificity and biological function. The knowledge gained from the biophysical and biochemical characterization of these complexes will allow us to design synthetic cadherins with specific affinities and mechanical strength, as well as photoswitchable adhesion interfaces to control tissue development and neuronal connectivity.
The Sotomayor group is looking for enthusiastic and motivated graduate and undergraduate students interested in doing experimental and/or computational research. Inquiries about positions in the group are welcomed.
Selected publications (see google scholar and researcherID)
“Sorting out a promiscuous superfamily: towards cadherin connectomics” M. Sotomayor, R. Gaudet, D. P. Corey. Trends in Cell Biology (2014), 24:524-536.
“Protocol for sortase-mediated construction of DNA-protein hybrids and functional nanostructures” M. A. Koussa, M. Sotomayor, W. Wong. Methods (2014), 67: 134-141.
“Structure of a Force-Conveying Cadherin Bond Essential for Inner-Ear Mechanotransduction” M. Sotomayor, W. A. Weihofen, R. Gaudet, and D. P. Corey. Nature (2012), doi:10.1038/nature11590.
“Constant electric field simulations of the membrane potential illustrated with simple systems” J. Gumbart, F. Khalili-Araghi, M. Sotomayor, and B. Roux. BBA – Biomembranes (2012), 1818:294-302.
“Structural Determinants of Cadherin-23 Function in Hearing and Deafness” M. Sotomayor*, W. A. Weihofen*, R. Gaudet, and D. P. Corey. Neuron (2010), 66:85-100, Cover article.
“The Allosteric Role of the Ca2+ Switch in Adhesion and Elasticity of C-Cadherin” M. Sotomayor and K. Schulten. Biophysical Journal (2008), 94:4621-4633.
“Single-Molecule Experiments in Vitro and in Silico” M. Sotomayor and K. Schulten. Science (2007), 316:1144-1148.
“Ion Conduction through MscS as Determined by Electrophysiology and Simulation” M. Sotomayor*, V. Vasquez*, E. Perozo, and K. Schulten. Biophysical Journal (2007), 92:886-902.
“Molecular Mechanisms of Cellular Mechanics” M. Gao, M. Sotomayor, E. Villa, E. Lee, and K. Schulten. Physical Chemistry-Chemical Physics (2006), 8:3692-3706.
“In Search of the Hair-Cell Gating Spring: Elastic Properties of Ankyrin and Cadherin Repeats” M. Sotomayor, D. P. Corey, and K. Schulten. Structure (2005) 13:669-682.