Modeling AFM-induced PEVK extension and the reversible unfolding of Ig/FNIII domains in single and multiple titin molecules.
Molecular elasticity is associated with a select number of polypeptides and proteins, such as titin, Lustrin A, silk fibroin, and spider silk dragline protein. In the case of titin, the globular (Ig) and non-globular (PEVK) regions act as extensible springs under stretch; however, their unfolding behavior and force extension characteristics are different. Using our time-dependent macroscopic method for simulating AFM-induced titin Ig domain unfolding and refolding, we simulate the extension and relaxation of hypothetical titin chains containing Ig domains and a PEVK region. Two different models are explored: 1) a series-linked WLC expression that treats the PEVK region as a distinct entropic spring, and 2) a summation of N single WLC expressions that simulates the extension and release of a discrete number of parallel titin chains containing constant or variable amounts of PEVK. In addition to these simulations, we also modeled the extension of a hypothetical PEVK domain using a linear Hooke's spring model to account for "enthalpic" contributions to PEVK elasticity. We find that the modified WLC simulations feature chain length compensation, Ig domain unfolding/refolding, and force-extension behavior that more closely approximate AFM, laser tweezer, and immunolocalization experimental data. In addition, our simulations reveal the following: 1) PEVK extension overlaps with the onset of Ig domain unfolding, and 2) variations in PEVK content within a titin chain ensemble lead to elastic diversity within that ensemble.
Zhang
B
B
Laboratory for Chemical Physics, Department of Chemistry, New York University, New York, New York 10010, USA.
Evans
J S
JS
D000595:Amino Acid Sequence; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D064211:Connectin; D004548:Elasticity; D005353:Fibronectins / Q000737:chemistry; D007136:Immunoglobulins / Q000737:chemistry; D066298:In Vitro Techniques; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D009124:Muscle Proteins / Q000737:chemistry*; D017510:Protein Folding; D011494:Protein Kinases / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
D064211:Connectin; D005353:Fibronectins; D007136:Immunoglobulins; D009124:Muscle Proteins; D011494:Protein Kinases