School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Sci Rep. 2018 Jan 16;8(1):844. doi: 10.1038/s41598-017-18933-3.
Recent experiments suggest that cellular crowding facilitates the target search dynamics of proteins on DNA, the mechanism of which is not yet known. By using large scale computer simulations, we show that two competing factors, namely the width of the depletion layer that separates the crowder cloud from the DNA molecule and the degree of protein-crowder crosstalk, act in harmony to affect the target search dynamics of proteins. The impacts vary from nonspecific to specific target search regime. During a nonspecific search, dynamics of a protein is only minimally affected, whereas, a significantly different behaviour is observed when the protein starts forming a specific protein-DNA complex. We also find that the severity of impacts largely depends upon physiological crowder concentration and deviation from it leads to attenuation in the binding kinetics. Based on extensive kinetic study and binding energy landscape analysis, we further present a comprehensive molecular description of the search process that allows us to interpret the experimental findings.
最近的实验表明，细胞拥挤有助于蛋白质在 DNA 上的靶标搜索动力学，但其机制尚不清楚。通过使用大规模计算机模拟，我们表明，两种竞争因素，即分离拥挤云与 DNA 分子的耗尽层的宽度和蛋白质-拥挤者的串扰程度，协同作用以影响蛋白质的靶标搜索动力学。这些影响从非特异性到特异性靶标搜索状态而变化。在非特异性搜索中，蛋白质的动力学仅受到最小的影响，而当蛋白质开始形成特定的蛋白质-DNA 复合物时，则会观察到明显不同的行为。我们还发现，影响的严重程度在很大程度上取决于生理拥挤者的浓度，并且偏离该浓度会导致结合动力学的衰减。基于广泛的动力学研究和结合能景观分析，我们进一步提出了搜索过程的全面分子描述，使我们能够解释实验结果。
