COMPUTATIONAL STUDIES OF GART

甘氨酰胺核糖核苷酸转甲酰基酶（GART）是一种重要的DNA嘌呤碱基生物合成酶。 它也是一个有吸引力的候选目标与抗菌剂或抗菌剂。 理解GART中的结构-功能关系是合理药物设计的第一步。 高分辨率的晶体结构数据和详细的动力学机制描述的酶促反应的可用性，使GART一个理想的模型系统，以调查显着的结构域-结构域的相互作用，是重要的结构形成和催化。 我们建议使用一种新的计算方法，这是基于求解线性化的Poisson-Boltzmann方程的理论计算的所有电离基团的GART的pKa值。 我们期望描绘的作用，负责单体-二聚体过渡的离子化基团，并了解的作用His 54，His 7，Glu 70，Tyr 67，Tyr 78，Tyr 115和其他可滴定的残基的过渡机制。 由于该计算将利用GART的X射线结构，我们期望阐明二聚化后构象变化的意义。 我们建议应用Monte Carlo和随机动力学方法（MC/SD）的组合来模拟pH依赖的无序环有序环/螺旋过渡残基110-131的Glu 70 Ala GART突变体和蛋白质的整体和其催化活性的局部构象转变的影响。

Glycinamide Ribonucleotide Transformylase (GART) is an important enzyme for the biosynthesis of purine bases for DNA. It is also an attractive candidate for targeting with antineoplastic or antimicrobial agents. Understanding of structure-function relations in GART is a first step for rational drug design. The availability of high resolution crystal structure data and detailed kinetic mechanisms describing the enzymatic reaction make GART an ideal model system to investigate significant domain-domain interactions that are important for structure formation and catalysis. We propose to theoretically calculate the pKa values of all ionizable groups of GART using a novel computational approach which is based on solving the linearized Poisson-Boltzmann equation. We expect to delineate the role of the ionizable groups that are responsible for the monomer-dimer transition and to understand the role His54, His7, Glu70, Tyr67, Tyr78, Tyr115 and other titratable residues in the mechanism of the transition. Since this calculation will utilize the X-ray structures of GART we expect to elucidate the significance of the conformational changes upon dimerization. We propose to apply a combination of Monte Carlo and Stochastic dynamics methods (MC/SD) to model the pH-dependent disordered loop-ordered loop/helix transition in residues 110-131 of the Glu70Ala GART mutant and the effect of the local conformational transition in the protein overall and its catalytic activity.