Modeling Transition Metal Ion Binding to Proteins

项目摘要/摘要 过渡金属(TM)离子在生物学中扮演着多种角色，目前存在于PDB中30%的结构中 与蛋白质的“有机”框架相比，这些离子的精确计算模型进化得更慢。 因此，对金属蛋白结构、功能和动力学的模拟研究相对滞后。 不含结构或功能TM离子的蛋白质。为了解决这个问题，巴尔干化的方法已经 在过去的几十年里，多个团队构建了基于不同变量的验证模型 许多标准不可用或仅在特定程序包中提供，这进一步使其难以集中 最佳实践。由于在Tm离子建模方面的这一差距，与以下相关的重要生物学问题 Tm离子动态平衡、金属中心组装、Tm/药物相互作用、配基缔合动力学和产物 金属酶的解离，利用TM的营养免疫攻击病原体 感染部位等是一个需要解决的重大挑战。通过开发健壮的计算 TMS的模型这些问题，尤其是专注于金属离子生物学的问题，将变得像 目前对于缺乏Tm离子的生物分子是可能的。 我们的首要目标是开发经过验证的经典力场模型，这些模型可以随时获得，可以 常规和准确地模拟TMS与蛋白质和水相结合的结构和热力学 解决方案，以解决涉及金属离子的关键生物学问题。我们的长期目标是 将一系列现有的TM建模方法整合到Amber中，然后验证和传播 各种方法供我们自己使用，也供社会使用。此外，在这项提案中，我们将适用 我们经过验证的模型可以模拟TM在模型和蛋白质金属结合部位的结合，探索TM的各个方面 离子动态平衡(TMIH)，并为原子力显微镜(AFM)提供分子水平的洞察 金属蛋白的分子研究。我们正在解决的基本生物物理问题是： 准确和常规地模拟TMS需要什么？金属离子的分子水平的细节是什么 蛋白质中的络合作用。在我们成功开发一流的键合金属离子力场的基础上 我们将创建下一代模型(重点关注非绑定表示)，这些模型可以 在理解TMS在生物过程中的关键作用方面被利用。

Project Summary/Abstract Transition metal (TM) ions play myriad roles in biology and are present in >30% of structures in the PDB yet the accurate computational modeling of these ions is less evolved than for the “organic” framework of proteins. Hence, the simulation of metalloprotein structure, function and dynamics is lagging behind related studies on proteins that do not contain structural or functional TM ions. To address this issue a Balkanized approach has been taken over the last several decades where multiple groups have built models validated based on varying criteria with many being unavailable or only available in specific packages further making it difficult to focus best practices. Because of this gap in the modeling of TM ions important biological problems associated with TM ion homeostasis, metal center assembly, TM/drug interactions, dynamics of ligand association and product dissociation in metalloenzymes, attacking pathogens using nutritional immunity via TM sequestration near infection sites, etc. are a significant challenge to address. Through the development of robust computational models of TMs these problems, amongst others, focused on metal ion biology will become as addressable as is currently possible for biological molecules lacking TM ions. Our over-arching goal is to develop validated classical force field models that are readily available that can routinely and accurately model the structure and thermodynamics of TMs bound to proteins and in aqueous solution in order to address critical biological questions involving metal ions. Our long-term goal is to incorporate a range of extant TM modeling approaches into AMBER and to then validate and disseminate the various methodologies for our own use and for that of the community. Moreover, in this proposal we will apply our validated models to simulate TM binding at model and at protein metal binding sites, explore aspects of TM ion homeostasis (TMIH) and provide molecular-level insights into Atomic Force Microscopy (AFM) single- molecule studies on metalloproteins. The fundamental overarching biophysical question we are addressing is: what is required to accurately and routinely model TMs and what are the molecular-level details of metal ion complexation in proteins. Building on our success with developing class-leading bonded metal ion force fields we will create next generation models (with a strong focus on nonbonded representations) that can be exploited in understanding the critical role of TMs in biological processes.