On the characterization of protein native state ensembles.

Describing and understanding the biological function of a protein requires a detailed structural and thermodynamic description of the protein's native state ensemble. Obtaining such a description often involves characterizing equilibrium fluctuations that occur beyond the nanosecond timescale. Capturing such fluctuations remains nontrivial even for very long molecular dynamics and Monte Carlo simulations. We propose a novel multiscale computational method to exhaustively characterize, in atomistic detail, the protein conformations constituting the native state with no inherent timescale limitations. Applications of this method to proteins of various folds and sizes show that thermodynamic observables measured as averages over the native state ensembles obtained by the method agree remarkably well with nuclear magnetic resonance data that span multiple timescales. By characterizing equilibrium fluctuations at atomistic detail over a broad range of timescales, from picoseconds to milliseconds, our method offers to complement current simulation techniques and wet-lab experiments and can impact our understanding and description of the relationship between protein flexibility and function.

描述和理解蛋白质的生物学功能需要对蛋白质本地态合奏的详细结构和热力学描述。获得这样的描述通常涉及表征纳秒时间尺度以外发生的平衡波动。即使在很长的分子动力学和蒙特卡洛模拟中，捕获这种波动仍然不足。我们提出了一种新型的多尺度计算方法，以详尽地表征原子的细节，构成本地状态的蛋白质构象没有固有的时间尺度限制。该方法在各种折叠和尺寸的蛋白质上的应用表明，该方法获得的热力学可观察结果是在该方法获得的天然状态集合上测得的平均值，与跨越多个时间表的核磁共振数据非常吻合。通过表征在整个时间尺度上，从picseconds到毫秒到毫秒的原子细节上的平衡波动，我们的方法提供了补充当前的仿真技术和湿LAB实验，并可能影响我们对蛋白质灵活性和功能之间关系的理解和描述。