KINETIC PATHWAY OF GROWTH FACTOR BINDING TO RECEPTOR

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 许多计算机模拟预测的受体特异性配体候选物在合成和测试后未能证明其计算的亲和力和特异性。我们假设，对接的三维（3D）投影的潜在的目标结合剂与三维投影的大分子疾病的目标可视化的计算机上的触摸和感觉反馈将使识别最佳的代理设计，并剔除次优的代理设计，合成之前。使用触觉反馈和对沿着动力学途径遇到的障碍物的定量测量将能够剔除不利的设计，使我们能够合成更灵敏和特异的分子探针，以支持叠加在患者的3D解剖图像上的患者的3D基因产物图像的投影。我们将通过合成携带新设计的配体的遗传探针并测量其对人类胰腺癌细胞上的靶受体的实际亲和力来验证这一假设。使用我们在Salk上的帐户，我们已经运行了EGF-EGFR动力学结合MD模拟，需要48小时才能收敛。结果与实验室观察一致，即EGF 20 -31不能结合，而EGF 32 -48结合并内化。现在，我们希望进行更大的计算额外的EGF片段结合EGFR与明确的水，这将需要更多的节点来完成在一个合理的时间。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Many receptor-specific ligand candidates predicted in silico fail to demonstrate their calculated affinity and specificity after synthesis and testing. We hypothesize that docking of three-dimensional (3D) projections of potential target binding agents with 3D projections of macromolecular disease targets visualized on a computer with touch and feel feedback will enable identification of optimal agent designs, and culling of suboptimal agent designs, prior to synthesis. The use of haptic feedback and quantitative measurements of obstacles encountered along the kinetic pathway will enable culling of unfavorable designs, allowing us to synthesize more sensitive and specific molecular probes to support the projection of 3D gene product images of patients superimposed on 3D anatomical images of patients. We will test this hypothesis by synthesizing a genetic probe carrying a newly designed ligand and measuring its actual affinity for the target receptors on human pancreatic cancer cells. Using our account on Salk, we have run EGF-EGFR kinetic binding MD simulations that required 48 hr to converge. The results agreed with bench observations that EGF20-31 failed to bind, while EGF32-48 bound and internalized. Now we wish to carry out larger calculations of additional EGF fragments binding to EGFR with explicit water, which will require more nodes to complete in a reasonable period.