Structural causes, control mechanisms and consequences of small-molecule protein binding promiscuity

细胞环境是一个拥挤、无情的环境，与试管中遇到的受控条件相去甚远。从热力学的角度来看，在这些条件下，蛋白质之间应该存在小分子的竞争，反之亦然。这种情况发生的程度受到蛋白质功能进化的影响，这不仅需要结合特定小分子的能力，还需要控制竞争的机制。多年来，这种小分子/蛋白质结合混杂的现象在很大程度上被忽视了，它对提高我们对分子识别、进化和细胞功能的认识至关重要。拟议的研究计划将开发必要的工具和资源，在系统水平上研究小分子蛋白质结合混杂的结构原因和控制机制。拟定研究计划的主要目标是：1。结合位点相似性检测方法的发展2：模拟蛋白质功能动态方面的方法的发展3。将实验和建模的蛋白质结构信息映射到重建的代谢网络中，以整合结构和系统生物学，并使用开发的方法来理解分子识别并在药物设计中利用它。该研究计划的新颖之处在于提出了强大的新方法，并从结构系统生物学的角度来理解分子识别。提出的研究计划将开发和整合结构计算生物学工具以及生物和化学信息学资源，代表了理解分子识别的新范式。该课程的跨学科性质将有助于形成来自不同背景的学生在化学，分子生物学，物理学和计算机科学的界面工作。

The cellular environment is a crowded, unforgiving environment far from the controlled conditions encountered in test tubes. From a thermodynamic point of view, in these conditions, there should be competition between proteins for small-molecules and vice versa. The extent to which this occurs is influenced by the evolution of protein function, that requires not only the ability to bind specific small molecules but also the mechanisms to keep in check the competition. This phenomenon of small-molecule/protein binding promiscuity has been largely ignored over the years and it is crucial in improving our knowledge of molecular recognition, evolution and cellular function. The proposed research program will develop the tools and resources necessary to study the structural causes and control mechanisms of small-molecule protein binding promiscuity at a systems level. The primary objectives of the proposed research program are: 1. The development of methods for the detection of binding site similarities 2: The development of methods for the simulation of dynamic aspects of protein function, and 3. The mapping of experimental and modelled protein structural information into reconstructed metabolic networks to integrate structural and systems biology and use of the methods developed to understand molecular recognition and exploit it in drug design. The novelty of the research plan lies in the powerful new methods proposed and their use to understanding molecular recognition from a structural systems biology point of view. The proposed research plan will develop and integrate structural computational biology tools as well as bio- and chemo-informatics resources and represents a new paradigm for understanding molecular recognition. The interdisciplinary nature of this program will contribute to the formation of students from diverse backgrounds to work at the interface of chemistry, molecular biology, physics and computer sciences.