Computational Core

我们将使用以前由我们的研究小组开发和测试的计算技术来研究DNA复制和相关的生化过程。这些计算机模拟将系统地检验由于不同因素引起的化学步骤激活势垒的变化，包括远距离PolB残基的点突变对p-y桥氧被-C X Y-基团取代的影响，其中X.Y=H、CH3、F、CI、Br或N3，以及引物或dNTP核苷酸的脱氧核糖残基中的取代。此外，基态和过渡态基态结合的计算将通过延长模拟时间的经过验证的计算策略进行研究。模拟的结果(包括TS结构和电荷分布以及模拟协议)将形成一个数据库，该数据库将包括许多可通过实验验证的预测以及用于生成这些预测的假设和理论模型的列表。这个数据库将可以在线访问，并将不断更新新的实验和计算结果，帮助选择最佳模型和模拟策略，并最终在原子水平上了解DNA聚合酶的重要功能性质。此外，比较研究将有助于选择最有效的方法进行计算抑制物和突变筛选。

We will use computational techniques that were previously developed and tested by our research group in studies of DNA replication and related biochemical processes. These computer simulations will systematically examine changes in the activation barrier of the chemical step due to different factors including the effects of point mutations of distant pol B residues, to substitutions of the p-y bridging oxygen by the - C X Y - groups where X. Y = H, CH3, F, CI, Br or N3, and substitutions in the deoxyribose residues of the primer or dNTP nucleotides. Additionally, calculations of the substrate binding in its ground- and transition-state configurations will be investigated by proven computational strategies with extended simulation times. The results of the simulations (including TS structures and charge distributions as well as simulation protocols) will form a database that will include numerous experimentally-testable predictions along with the list of the assumptions and theoretical models that were used to generate these predictions. This database, which will be made accessible online, will be continually updated with new experimental and computational results, helping in selecting the best models and simulation strategies, and eventually to understanding of the functionally important properties of DNA polymerases at the atomic level. Additionally, the comparative studies will help in selecting the most effective approach for computational inhibitor and mutational screening.