温控分子动力学研究微管蛋白活性肽链的折叠机制

运用温控和常温分子动力学方法, 研究了微管蛋白活性部位Pep1-28肽链的折叠机制, 总模拟时间为380.0 ns. 对于温控分子动力学, 逐渐降温可以清晰显示Pep1-28肽链的折叠途径, 发生明显折叠的温度约为550 K, 其折叠和去折叠可逆机制为U(>1200 K)←→I1(1200-1000 K)←→I2(800 K)←→I3(600 K)←→I4(450 K)←→F1(400 K)←→F2(300 K), 其中U为去折叠态构象, I1、I2、I3和I4是折叠过程中的四个重要的中间态构象, F1和F2是两个结构相近的折叠态构象. 对于常温(300 K)分子动力学, 其构象转变和折叠过程相当迅速, 很难观察到有效、稳定的中间态构象. 尤其引人注意的是, 其折叠态结构陷入了能量局域极小点, 与温控(300 K)的有较大差异, 两者能量差高达297.53 kJ·mol-1. 可见, 温控分子动力学方法不仅清晰地显示多肽和蛋白质折叠过程的重要中间态构象, 为折叠和去折叠机制提供直接、可靠的依据, 而且还有助于跨越较高的构象能垒, 促使多肽和蛋白质折叠以形成全局能量最低的稳定结构.

Temperature-Controlled Molecular Dynamics Studies on the Folding Mechanism of the Tubulin Active Peptides

Using temperature controlled and normal temperature molecular dynamics methods, an in-depth study
was undertaken on the folding mechanismof the tubulin active peptide (Pep1-28). The total simulation time was 380.0 ns. We found a clear folding pathway by gradually decreasing the temperature using temperature controlled molecular dynamics simulations. Noticeable folding was observed at about 550 K and reversible folding and unfolding mechanisms were determined as U(>1200 K)←→←→I1(1200-1000 K)←→I2(800 K)←→I3(600 K)←→I4(450 K)←→F1(400 K)←→F2 (300 K), where U is an unfolded conformation and I1, I2, I3, and I4 are four important intermediates in the folding process. F1 and F2 are two folded conformations with similar structures. Conformational transformation and the folding process take place very quickly in normal temperature molecular dynamics, causing great difficulty in observing effective and stable intermediate conformations. The normal temperature molecular dynamics folds into a local energy minimum with the structure having severe discrepancies with that of the temperature controlled (300 K). The energy difference between these two folded structures was calculated to be as high as 297.53 kJ·mol-1. Therefore, the temperature controlled molecular dynamics method can provide direct and reliable proof for folding and unfolding by presenting the important intermediate conformations and can also induce folding towards the global lowest-energy conformation by crossing over high energy barriers.