Mechanosensing
Cells explore their environment by sensing and responding to mechanical forces. Many fundamental cellular processes, such as cell migration, differentiation, and homeostasis, take advantage of this sensing mechanism. At molecular level mechanosensing is mainly driven by mechanically active proteins. These proteins are able to sense and respond to forces by, e.g., undergoing conformational changes, exposing cryptic binding sites, or even by becoming more tightly bound to one another. In humans, defective responses to forces are known to cause a plethora of pathological conditions, including cardiac failure, pulmonary injury and are also linked to cancer. Microorganisms also take advantage of mechano-active proteins and proteins complexes. Employing single-molecule force spectroscopy with an atomic force microscope (AFM) and steered molecular dynamics (SMD) simulations we have investigated force propagation pathways through a mechanically active protein complexes.Spotlight: Stretching Muscle (Jan 2001)
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Water can act as a conformational lubricant for protein folding. The giant muscle protein titin is a roughly 30,000 amino acid long filament which plays a number of important roles in contraction and elasticity. For example, upon stretching in muscle some of titin's protein domains can unfold one-by-one permitting titin to retain elastic properties in muscle over a very wide range of length. To examine in atomic detail the dynamics and structure-function relationships of this behavior, SMD simulations of force-induced titin domain unfolding were performed in close collaboration with atomic force microscopy observations. The simulations led to the discovery that water molecules play an essential role in breaking sets of hydrogen bonds that control the unfolding of titin's domains (see resulting publication).
