Campitelli Paul, Ozkan S Banu
Department of Physics and Center for Biological Physics, Arizona State University, Tempe, AZ 85287, USA.
Entropy (Basel). 2020 Jun 16;22(6):667. doi: 10.3390/e22060667.
Understanding the underlying mechanisms behind protein allostery and non-additivity of substitution outcomes (i.e., epistasis) is critical when attempting to predict the functional impact of mutations, particularly at non-conserved sites. In an effort to model these two biological properties, we extend the framework of our metric to calculate dynamic coupling between residues, the Dynamic Coupling Index (DCI) to two new metrics: (i) EpiScore, which quantifies the difference between the residue fluctuation response of a functional site when two other positions are perturbed with random Brownian kicks simultaneously versus individually to capture the degree of cooperativity of these two other positions in modulating the dynamics of the functional site and (ii) DCI, which measures the degree of asymmetry between the residue fluctuation response of two sites when one or the other is perturbed with a random force. Applied to four independent systems, we successfully show that EpiScore and DCI can capture important biophysical properties in dual mutant substitution outcomes. We propose that allosteric regulation and the mechanisms underlying non-additive amino acid substitution outcomes (i.e., epistasis) can be understood as emergent properties of an anisotropic network of interactions where the inclusion of the full network of interactions is critical for accurate modeling. Consequently, mutations which drive towards a new function may require a fine balance between functional site asymmetry and strength of dynamic coupling with the functional sites. These two tools will provide mechanistic insight into both understanding and predicting the outcome of dual mutations.
在试图预测突变的功能影响时，尤其是在非保守位点，了解蛋白质变构和替代结果的非加性（即上位性）背后的潜在机制至关重要。为了对这两种生物学特性进行建模，我们将用于计算残基之间动态耦合的指标框架——动态耦合指数（DCI）扩展到两个新指标：（i）上位性得分（EpiScore），它量化了功能位点的残基波动响应在另外两个位置同时受到随机布朗运动冲击与单独受到冲击时的差异，以捕捉这另外两个位置在调节功能位点动态方面的协同程度；（ii）DCI，它测量当两个位点中的一个或另一个受到随机力干扰时，这两个位点的残基波动响应之间的不对称程度。应用于四个独立系统，我们成功表明上位性得分和DCI能够捕捉双突变替代结果中的重要生物物理特性。我们提出，变构调节和非加性氨基酸替代结果（即上位性）背后的机制可以理解为各向异性相互作用网络的涌现特性，其中完整的相互作用网络对于准确建模至关重要。因此，驱动产生新功能的突变可能需要在功能位点不对称性和与功能位点的动态耦合强度之间取得精细平衡。这两个工具将为理解和预测双突变结果提供机制性见解。
