High Performance Computing Research Department, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
J Phys Chem B. 2010 Mar 11;114(9):3242-53. doi: 10.1021/jp911124z.
Single-molecule experiments are allowing researchers to track the evolution of a few order parameters characterizing complex biomolecules. At fine temporal resolution, artifacts of unresolved degrees of freedom, for example, those induced by collective molecular motion, often influence the dynamics. Reliably detecting subtle changes in dynamics at the nanoscale can be difficult due to the inherent stochasticity, but such changes can have relevance to understanding complex enzyme kinetics. Surrogate models can be used to summarize the information content in single-molecule time series (containing fluctuations occurring over multiple time scales). The focus in this article is on detecting slow time scale changes through the use of the surrogates. The conditional density, associated with the surrogates, allows one to formulate quantitative hypothesis tests which can detect the influence of unresolved coordinates in cases where the dynamics are modulated subtly. The relevance of quantitative (and appropriate) testing methods to analyze single-molecule time series is discussed and demonstrated. A brief discussion on some merits of using frequentist (versus Bayesian) time series methods to analyze single-molecule data is also presented. Idealized simulations mimicking features relevant to some enzyme systems where an "unresolved conformational coordinate" slowly evolves (1) with inertia and (2) diffusively are studied in the nonstationary (nonergodic) setting; however, the findings are also relevant to experimentally measured time series and stationary signals.
单分子实验使研究人员能够跟踪几个描述复杂生物分子的序参数的演化。在精细的时间分辨率下，未解析自由度的伪影（例如由集体分子运动引起的伪影）通常会影响动力学。由于固有的随机性，可靠地检测纳米尺度上动力学的微妙变化可能很困难，但这些变化可能与理解复杂的酶动力学有关。替代模型可用于总结单分子时间序列中的信息含量（包含在多个时间尺度上发生的波动）。本文的重点是通过使用替代模型来检测慢时间尺度变化。与替代相关的条件密度允许人们制定定量假设检验，这些检验可以在动力学被微妙地调制的情况下检测到未解析坐标的影响。讨论并证明了定量（和适当）检验方法对分析单分子时间序列的相关性。还简要讨论了使用频率主义（与贝叶斯）时间序列方法分析单分子数据的一些优点。在非平稳（非遍历）设置中研究了理想化的模拟，这些模拟模拟了一些酶系统的特征，其中“未解析构象坐标”（1）具有惯性和（2）扩散地缓慢演变；然而，这些发现也与实验测量的时间序列和稳定信号相关。
