Probing antibody internal dynamics with fluorescence anisotropy and molecular dynamics simulations.
Probing antibody internal dynamics with fluorescence anisotropy and molecular dynamics simulations.
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作者：
Kortkhonjia E;Brandman R;Zhou JZ;Voelz VA;Chorny I;Kabakoff B;Patapoff TW;Dill KA;Swartz TE
抗体的溶液动力学对抗体的功能至关重要。我们通过将IgG1上的时间分辨荧光各向异性实验与显性水中超过2微秒的全原子分子动力学（MD）模拟相结合，探索抗体分子的内部溶液动力学，比以前的模拟多一个数量级。我们用互信息熵量来分析相关运动，并在马尔可夫状态模型中考察状态转移率，给出运动的粗粒度描述符。我们的MD模拟表明，虽然存在许多强烈相关的运动，但抗体具有高度的灵活性，Fab和Fc结构域不断形成和破坏接触，包括极性和非极性。我们发现，盐桥会断裂和重建，但并不总是与相同的伙伴。虽然在明确的水中的MD模拟给出了正确的运动时间尺度，但模拟的运动速度比实验快3倍左右。总的来说，出现的情况是抗体不是简单地围绕原子接触的单一状态波动。相反，在这些大分子中，不同的原子在不同的运动中接触。
The solution dynamics of antibodies are critical to antibody function. We explore the internal solution dynamics of antibody molecules through the combination of time-resolved fluorescence anisotropy experiments on IgG1 with more than two microseconds of all-atom molecular dynamics (MD) simulations in explicit water, an order of magnitude more than in previous simulations. We analyze the correlated motions with a mutual information entropy quantity, and examine state transition rates in a Markov-state model, to give coarse-grained descriptors of the motions. Our MD simulations show that while there are many strongly correlated motions, antibodies are highly flexible, with Fab and Fc domains constantly forming and breaking contacts, both polar and non-polar. We find that salt bridges break and reform, and not always with the same partners. While the MD simulations in explicit water give the right time scales for the motions, the simulated motions are about 3-fold faster than the experiments. Overall, the picture that emerges is that antibodies do not simply fluctuate around a single state of atomic contacts. Rather, in these large molecules, different atoms come in contact during different motions.