Random Walk Enzymes: Information Theory, Quantum Isomorphism, and Entropy Dispersion
Random Walk Enzymes: Information Theory, Quantum Isomorphism, and Entropy Dispersion
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随机游走酶：信息论、量子同构和熵色散
DOI：
10.1021/acs.jpca.9b00910
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Goodman, Myron F.
中科院分区：
文献类型：
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作者：
Mak, Chi H.;Pham, Phuong;Goodman, Myron F.
激活诱导的脱氧胞苷脱氨酶（AID）是人体免疫系统中的关键酶。AID结合并催化免疫球蛋白（IG）基因上的随机点突变，通过随机游走运动导致IG基因序列多样化，扫描胞苷并将其转化为尿嘧啶。AID在其底物DNA序列上沉积的突变模式可以被解释为随机二进制字，并且这种随机生成的突变DNA序列库的信息含量可以通过其熵来度量。在本文中，我们推导出这个熵的解析公式，并表明随机扫描+催化动力学的AID控制的特征长度，取决于扩散系数的AID和催化速率。实验表明，脱氨速率具有序列上下文依赖性，其中在具有较高密度的可变位点的DNA序列上以较高强度产生突变。我们推导出这个经典系统和量子力学模型之间的同构，并使用这种同构来解释为什么AID似乎集中在具有较高浓度的脱氨位点的区域上进行扫描。使用路径积分蒙特卡罗模拟的量子同构系统，我们证明了如何AID的扫描确实取决于上下文的DNA序列，以及这如何影响所产生的突变体克隆库的熵。检查实验产生的克隆库的熵的详细功能，我们提供了明确的证据表明，其基板DNA上的AID的随机游走集中在热点附近。应用于实验数据的模型计算表明，所观察到的每个位点的突变频率显示类似的上下文依赖性，在实验中观察到的，其中热图案位于相邻的几种不同类型的热和冷图案。
Activation-induced deoxycytidine deaminase (AID) is a key enzyme in the human immune system. AID binds to and catalyzes random point mutations on the immunoglobulin (Ig) gene, leading to diversification of the Ig gene sequence by random walk motions, scanning for cytidines and turning them to uracils. The mutation patterns deposited by AID on its substrate DNA sequences can be interpreted as random binary words, and the information content of this stochastically generated library of mutated DNA sequences can be measured by its entropy. In this paper, we derive an analytical formula for this entropy and show that the stochastic scanning + catalytic dynamics of AID is controlled by a characteristic length that depends on the diffusion coefficient of AID and the catalytic rate. Experiments showed that the deamination rates have a sequence context dependence, where mutations are generated at higher intensities on DNA sequences with higher densities of mutable sites. We derive an isomorphism between this classical system and a quantum mechanical model and use this isomorphism to explain why AID appears to focus its scanning on regions with higher concentrations of deaminable sites. Using path integral Monte Carlo simulations of the quantum isomorphic system, we demonstrate how AID’s scanning indeed depends on the context of the DNA sequence and how this affects the entropy of the library of generated mutant clones. Examining detailed features in the entropy of the experimentally generated clone library, we provide clear evidence that the random walk of AID on its substrate DNA is focused near hot spots. The model calculations applied to the experimental data show that the observed per-site mutation frequencies display similar contextual dependences as observed in the experiments, in which hot motifs are located adjacent to several different types of hot and cold motifs.