Files in this item



application/pdf3301228.pdf (5MB)Restricted to U of Illinois
(no description provided)PDF


Title:Life Under Tension: Computational Studies of Proteins Involved in Mechanotransduction
Author(s):Sotomayor, Marcos Manuel
Doctoral Committee Chair(s):Nigel Goldenfeld
Department / Program:Physics
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Physics, Molecular
Abstract:Living organisms rely on macroscopic and microscopic structures that produce and transform force: from mechanical motion of our muscles and bones to sound transduction and cell volume regulation, handling of forces is essential to life. Investigation of the microscopic machinery behind force generation and transduction in the cell has only become possible with recent advances in x-ray crystallography, nuclear magnetic resonance spectroscopy, single-molecule force spectroscopy, and computer modeling. In this thesis, molecular dynamics simulations have been used to study proteins that transform forces into biochemical signals (mechanotransduction). The first protein studied is the mechanosensitive channel of small conductance MscS. This membrane channel has been proposed to act as a safety valve during osmotic shock, facilitating the release of ions and small solutes upon increase in membrane tension, thereby preventing bacterial cells from bursting. The second set of proteins studied are ankyrin and cadherin repeats, likely forming part of the transduction apparatus in hearing and other mechanical senses. Simulations of all these proteins went beyond the standard approach in which only equilibrium properties are monitored; we adopted and developed strategies in which external electric fields and forces are used to probe their response and function and at the same time produce verifiable predictions. The outcome of the simulations performed on MscS, in close collaborations with experimentalists, allowed us to establish conduction properties of different conformations and propose structural models of MscS's open and closed states. Simulations of ankyrin and cadherin repeats focused on their elastic properties, resulting in the discovery and prediction of ankyrin's tertiary and secondary structure elasticity (later on corroborated by atomic force microscopy experiments), and the discovery of a novel form of secondary structure elasticity mediated by calcium ions in cadherins. Simulations also revealed how calcium ions control cadherin's shape and the availability of key residues involved in cell-cell adhesion, suggesting a conceptual framework for interpreting mutations in cadherin calcium binding motifs causing hereditary deafness. Overall, simulations provided a unique nanoscopic view of the dynamics and function of some of the proteins involved in mechanotransduction.
Issue Date:2007
Description:178 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2007.
Other Identifier(s):(MiAaPQ)AAI3301228
Date Available in IDEALS:2015-09-25
Date Deposited:2007

This item appears in the following Collection(s)

Item Statistics