Lee Eric H, Hsin Jen, Mayans Olga, Schulten Klaus
Center for Biophysics and Computational Biology and Beckman Institute, College of Medicine, Department of Physics and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Biophys J. 2007 Sep 1;93(5):1719-35. doi: 10.1529/biophysj.107.105528. Epub 2007 May 11.
The giant protein titin, which is responsible for passive elasticity in muscle fibers, is built from approximately 300 regular immunoglobulin-like (Ig) domains and FN-III repeats. While the soft elasticity derived from its entropic regions, as well as the stiff mechanical resistance derived from the unfolding of the secondary structure elements of Ig- and FN-III domains have been studied extensively, less is known about the mechanical elasticity stemming from the orientation of neighboring domains relative to each other. Here we address the dynamics and energetics of interdomain arrangement of two adjacent Ig-domains of titin, Z1, and Z2, using molecular dynamics (MD) simulations. The simulations reveal conformational flexibility, due to the domain-domain geometry, that lends an intermediate force elasticity to titin. We employ adaptive biasing force MD simulations to calculate the energy required to bend the Z1Z2 tandem open to identify energetically feasible interdomain arrangements of the Z1 and Z2 domains. The finding is cast into a stochastic model for Z1Z2 interdomain elasticity that is generalized to a multiple domain chain replicating many Z1Z2-like units and representing a long titin segment. The elastic properties of this chain suggest that titin derives so-called tertiary structure elasticity from bending and twisting of its domains. Finally, we employ steered molecular dynamics simulations to stretch individual Z1 and Z2 domains and characterize the so-called secondary structure elasticity of the two domains. Our study suggests that titin's overall elastic response at weak force stems from a soft entropic spring behavior (not described here), from tertiary structure elasticity with an elastic spring constant of approximately 0.001-1 pN/A and, at strong forces, from secondary structure elasticity.
巨大的肌联蛋白负责肌肉纤维的被动弹性，它由大约300个规则的免疫球蛋白样（Ig）结构域和纤连蛋白III型重复序列组成。虽然源于其熵区域的软弹性以及源于Ig和FN-III结构域二级结构元件展开的刚性机械阻力已得到广泛研究，但对于相邻结构域彼此相对取向产生的机械弹性了解较少。在这里，我们使用分子动力学（MD）模拟来研究肌联蛋白两个相邻Ig结构域Z1和Z2的结构域间排列的动力学和能量学。模拟揭示了由于结构域-结构域几何形状导致的构象灵活性，这赋予了肌联蛋白中等的力弹性。我们采用自适应偏置力MD模拟来计算将Z1Z2串联打开所需的能量，以确定Z1和Z2结构域在能量上可行的结构域间排列。这一发现被纳入一个Z1Z2结构域间弹性的随机模型，该模型被推广到一个复制许多Z1Z2样单元并代表长肌联蛋白片段的多结构域链。该链的弹性特性表明，肌联蛋白从其结构域的弯曲和扭转中获得了所谓的三级结构弹性。最后，我们采用定向分子动力学模拟来拉伸单个Z1和Z2结构域，并表征这两个结构域的所谓二级结构弹性。我们的研究表明，肌联蛋白在弱力下的整体弹性响应源于软熵弹簧行为（此处未描述）、弹性弹簧常数约为0.001 - 1 pN/Å的三级结构弹性，以及在强力下的二级结构弹性。
