Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
PLoS One. 2012;7(2):e32011. doi: 10.1371/journal.pone.0032011. Epub 2012 Feb 16.
Promiscuity, the basis for the evolution of new functions through 'tinkering' of residues in the vicinity of the catalytic site, is yet to be quantitatively defined. We present a computational method Promiscuity Indices Estimator (PROMISE)--based on signatures derived from the spatial and electrostatic properties of the catalytic residues, to estimate the promiscuity (PromIndex) of proteins with known active site residues and 3D structure. PromIndex reflects the number of different active site signatures that have congruent matches in close proximity of its native catalytic site, the quality of the matches and difference in the enzymatic activity. Promiscuity in proteins is observed to follow a lognormal distribution (μ = 0.28, σ = 1.1 reduced chi-square = 3.0E-5). The PROMISE predicted promiscuous functions in any protein can serve as the starting point for directed evolution experiments. PROMISE ranks carboxypeptidase A and ribonuclease A amongst the more promiscuous proteins. We have also investigated the properties of the residues in the vicinity of the catalytic site that regulates its promiscuity. Linear regression establishes a weak correlation (R(2)∼0.1) between certain properties of the residues (charge, polar, etc) in the neighborhood of the catalytic residues and PromIndex. A stronger relationship states that most proteins with high promiscuity have high percentages of charged and polar residues within a radius of 3 Å of the catalytic site, which is validated using one-tailed hypothesis tests (P-values∼0.05). Since it is known that these characteristics are key factors in catalysis, their relationship with the promiscuity index cross validates the methodology of PROMISE.
变异性，即通过“修补”催化部位附近的残基来实现新功能进化的基础，尚未被定量定义。我们提出了一种计算方法——变异性指数估算器（PROMISE），它基于来自催化残基空间和静电特性的特征来估算具有已知活性部位残基和 3D 结构的蛋白质的变异性（PromIndex）。PromIndex 反映了在其天然催化部位附近有多少个具有一致匹配的不同活性部位特征，以及匹配的质量和酶活性的差异。蛋白质的变异性被观察到遵循对数正态分布（μ=0.28，σ=1.1 约化卡方=3.0E-5）。PROMISE 预测的任何蛋白质的变异性功能都可以作为定向进化实验的起点。PROMISE 将羧肽酶 A 和核糖核酸酶 A 列为更具变异性的蛋白质。我们还研究了调节其变异性的催化部位附近残基的性质。线性回归确定了催化残基附近残基的某些性质（电荷、极性等）与 PromIndex 之间存在弱相关性（R2∼0.1）。更强的关系表明，大多数具有高变异性的蛋白质在催化部位 3Å 半径内具有高比例的带电荷和极性残基，这通过单侧假设检验（P 值∼0.05）得到验证。由于已知这些特性是催化的关键因素，它们与变异性指数的关系交叉验证了 PROMISE 方法的有效性。
