The prediction of protein mutations that affect function may be exploited for multiple uses. In the context of disease variants, the prediction of compensatory mutations that reestablish functional phenotypes could aid in the development of genetic therapies. In this work, we present an integrated approach that combines coevolutionary analysis and molecular dynamics (MD) simulations to discover functional compensatory mutations. This approach is employed to investigate possible rescue mutations of a poly(ADP-ribose) polymerase 1 (PARP1) variant, PARP1 V762A, associated with lung cancer and follicular lymphoma. MD simulations show PARP1 V762A exhibits noticeable changes in structural and dynamical behavior compared with wild-type (WT) PARP1. Our integrated approach predicts A755E as a possible compensatory mutation based on coevolutionary information, and molecular simulations indicate that the PARP1 A755E/V762A double mutant exhibits similar structural and dynamical behavior to WT PARP1. Our methodology can be broadly applied to a large number of systems where single-nucleotide polymorphisms have been identified as connected to disease and can shed light on the biophysical effects of such changes as well as provide a way to discover potential mutants that could restore WT-like functionality. This can, in turn, be further utilized in the design of molecular therapeutics that aim to mimic such compensatory effect.

影响功能的蛋白质突变的预测可用于多种用途。在疾病变异的背景下，预测重建功能表型的补偿性突变可能有助于基因疗法的开发。在这项工作中，我们提出了一种综合方法，结合了协同进化分析和分子动力学（MD）模拟来发现功能补偿突变。该方法用于研究与肺癌和滤泡性淋巴瘤相关的聚（ADP-核糖）聚合酶 1 (PARP1) 变体 PARP1 V762A 可能的拯救突变。MD 模拟显示，与野生型 (WT) PARP1 相比，PARP1 V762A 在结构和动力学行为方面表现出显着变化。我们的综合方法根据共同进化信息预测 A755E 作为可能的补偿突变，分子模拟表明 PARP1 A755E/V762A 双突变体表现出与 WT PARP1 相似的结构和动力学行为。我们的方法可以广泛应用于大量系统，其中单核苷酸多态性已被确定与疾病有关，并且可以阐明此类变化的生物物理影响，并提供一种发现可以恢复 WT-的潜在突变体的方法。就像功能一样。反过来，这可以进一步用于设计旨在模拟这种补偿效应的分子疗法。