KINETIC PATHWAY OF GROWTH FACTOR BINDING TO RECEPTOR

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 许多在Silico中预测的受体特异性配体候选经过合成和测试后，未能证明它们计算出的亲和力和特异性。我们假设，潜在靶标结合剂的三维(3D)投影与在具有触摸和感觉反馈的计算机上可视化的大分子疾病靶标的3D投影的对接，将使在合成之前能够识别最佳的试剂设计，并剔除次优的试剂设计。使用触觉反馈和对运动路径上遇到的障碍进行定量测量将能够剔除不利的设计，使我们能够合成更敏感和特定的分子探针，以支持将患者的3D基因产品图像投影到患者的3D解剖图像上。我们将通过合成一种携带新设计的配体的遗传探针，并测量其与人胰腺癌细胞上目标受体的实际亲和力来检验这一假设。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。结果与实验观察结果一致，即EGF20-31未能结合，而EGF32-48结合并内化。现在我们希望对与EGFR结合的更多EGF片段进行更大的计算，这将需要更多的节点在合理的时间内完成。

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.