Modeling evolutionary landscapes: Mutational stability, topology, and superfunnels in sequence space
Modeling evolutionary landscapes: Mutational stability, topology, and superfunnels in sequence space
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DOI：
10.1073/pnas.96.19.10689
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发表时间：
1999-09-14
影响因子：
11.1
通讯作者：
Chan, HS
中科院分区：
文献类型：
--
作者：
Bornberg-Bauer, E;Chan, HS
中性或近中性条件下的随机突变通过考虑“中性网”上的合理进化轨迹来研究-即，通过编码相同基态结构（表型）的单点突变相互连接的序列（基因型）的集合。我们使用简单的精确格模型之间的映射序列和构象空间。基于模型链内相互作用的状态密度由穷举构象计数确定，我们比较了两个非常不同的相互作用方案的结果，以确定结论的鲁棒性。在这两个模型中，大多数中性网络中的序列都围绕着一个具有最大突变稳定性的“原型序列”，容忍最大数量的中性突变。一般的分析考虑表明，这些拓扑结构本身导致较高的稳态进化种群的原型序列。平均而言，原生热力学稳定性在原型序列处朝向最大值增加，导致在序列空间中原生稳定性的漏斗状布置。这些观察结果提供了一个统一的角度对序列设计，天然稳定性，和突变的蛋白质的稳定性，这些原则是概括从天然稳定性的任何措施的健身提供了它的变化相对于突变基本上是平滑的。
Random mutations under neutral or near-neutral conditions are studied by considering plausible evolutionary trajectories on "neutral nets"-i.e., collections of sequences (genotypes) interconnected via single-point mutations encoding for the same ground-state structure (phenotype). We use simple exact lattice models for the mapping between sequence and conformational spaces. Densities of states based on model intrachain interactions are determined by exhaustive conformational enumeration, We compare results from two very different interaction schemes to ascertain robustness of the conclusions. In both models, sequences in a majority of neutral nets center around a single "prototype sequence" of maximum mutational stability, tolerating the largest number of neutral mutations. General analytical considerations show that these topologies by themselves lead to higher steady-state evolutionary populations at prototype sequences. On average, native thermodynamic stability increases toward a maximum at the prototype sequence, resulting in funnel-like arrangements of native stabilities in sequence space. These observations offer a unified perspective on sequence design, native stability, and mutational stability of proteins, These principles are generalizable from native stability to any measure of fitness provided that its variation with respect to mutations is essentially smooth.