Tiana G, Broglia R A
Department of Physics, University of Milano and INFN, via Celoria 16, 20133 Milano, Italy.
Proteins. 2009 Sep;76(4):895-910. doi: 10.1002/prot.22395.
Progress in understanding protein folding allows to simulate, with atomic detail, the evolution of amino-acid sequences folding to a given native conformation. A particularly attractive example is the HIV-1 protease, main target of therapies to fight AIDS, which under drug pressure is able to develop resistance within few months from the starting of therapy. By comparing the results of simulations of the evolution of the protease with the corresponding proteomic data, one can approximately determine the value of the associated evolution pressure under which the enzyme has become and, as a consequence, map out the energy landscape in sequence space of the HIV-1 protease. It is found that there are several families of sequences folding to the native conformations of the enzyme. Each of these families are characterized by different sets of highly conserved ("hot") amino acids which play a critical role in the folding and stability of the protease. There are two main possibilities for the virus to move from one family to a different one: (a) in a single generation, through the concerted mutations of the hot amino acids, a highly unlikely event, (b) through a folding path (if it exists), again a very improbable event. In fact, the number of generations needed by the virus to change stepwise its sequence from one family to another is astronomically large. These results point to the "hot" segments of the protease as promising targets for a nonconventional inhibition strategy, likely not to create resistance.
对蛋白质折叠的理解取得进展，使得能够在原子层面模拟氨基酸序列折叠成特定天然构象的过程。一个特别引人关注的例子是HIV-1蛋白酶，它是抗击艾滋病疗法的主要靶点，在药物压力下，从治疗开始后的几个月内就能产生耐药性。通过将蛋白酶进化模拟结果与相应的蛋白质组学数据进行比较，可以大致确定该酶形成时相关进化压力的值，进而描绘出HIV-1蛋白酶序列空间中的能量景观。研究发现，有几个序列家族能够折叠成该酶的天然构象。这些家族中的每一个都有不同的高度保守（“热点”）氨基酸集合，它们在蛋白酶的折叠和稳定性中起着关键作用。病毒从一个家族转移到另一个家族主要有两种可能性：（a）在一代中，通过热点氨基酸的协同突变，这是极不可能发生的事件；（b）通过折叠路径（如果存在），这同样是极不可能发生的事件。事实上，病毒逐步将其序列从一个家族改变到另一个家族所需的代数多得惊人。这些结果表明，蛋白酶的“热点”区域是一种非常规抑制策略的有希望的靶点，可能不会产生耐药性。
