Using side-chain vibrational interactions as a computational model for protein allostery

报道人类基因组计划成功的媒体报道强调了DNA分子的重要性，但关于蛋白质方面的许多研究工作的报道相对较少。虽然DNA对于遗传信息的存储和传输是必不可少的，但活细胞的重要生命过程主要是由数千种不同的蛋白质分子完成的，这些分子提供结构形式、运动能力、加速化学反应和信号传输(例如，神经突触中的激素和膜蛋白)。蛋白质可以改变形状，通常被描述为分子马达，可以与其他蛋白质和称为配体(例如，药物)的各种较小分子相互作用或结合。与配体结合有关的一个重要现象称为变构：配体结合启动蛋白质内部的波动或某种类型的信息传递，最终导致蛋白质其他地方的结构变化，这种变化允许它与不同的分子相互作用。尽管在研究界已经提出了几个想法，但变构的确切机制还没有完全理解。*我们的研究项目将通过将蛋白质的内部视为一组使用振动耦合相互作用的实体来进行变构的计算建模。计算分析将确定各种偶合的强度，以预测是否存在解释变构行为的内部路径。当这一目标实现后，下一步是通过调查这些途径能否很好地解释先前研究过的已知变构蛋白质的行为，来评估预测的成功。该项目的最终目标将是确定当蛋白质被修饰时，变构是如何受到影响或消除的，就像癌症等疾病状态下可能发生的那样。*最终目标的研究价值是了解氨基酸突变可能导致蛋白质变构功能障碍的原因。总的来说，对变构的更全面的理解将对药物设计有许多实际的好处，特别是通过传递变构调节起作用的药物。这些洞察力和算法策略将对加拿大制药业具有重大价值，因为加拿大制药业一直需要创新技术来处理新的生物目标。

Media reports covering the success of the Human Genome Project have stressed the importance of DNA molecules, but there has been relatively little reporting about the many research efforts dealing with proteins. While DNA is essential for the storage and transmission of genetic information, the significant life processes of a living cell are primarily accomplished by the thousands of different protein molecules that provide structural form, movement capabilities, acceleration of chemical reactions, and signal transmission (for example, hormones and membrane proteins in neural synapses). Proteins can change shape and are often described as molecular motors that can interact or bind with other proteins and various smaller molecules called ligands (for example, drugs). An important phenomenon that is often associated with ligand binding is called allostery: ligand binding initiates an internal fluctuation or some type of information transfer within the protein culminating in a structural change elsewhere in the protein, and this change allows it to interact with a different molecule. The exact mechanism underlying allostery is not yet fully understood even though several ideas have been set forth in the research community.****Our research project will undertake the computational modeling of allostery by treating the interior of a protein as a set of entities that interact using vibrational couplings. The computational analysis will determine the strength of various couplings to predict the existence of internal pathways that would explain the allosteric behaviour. When this goal has been achieved the next step is to evaluate the success of the predictions by investigating how well these pathways can explain the behaviour of previously studied proteins that are known to be allosteric. The final goal of the project would be to establish how allostery is compromised or eliminated when the protein is modified, as might happen in disease states such as cancer.****The research value of the final goal is to understand how protein allosteric dysfunctionality may arise from amino acid mutations. In general, a more comprehensive understanding of allostery would have many practical benefits for drug design, in particular, drugs that work by imparting allosteric modulation. These insights and algorithmic strategies will have significant value for the Canadian pharmaceutical industry, which is in constant need of innovative techniques to handle new biological targets.******