Forecasting protein evolution by integrating birth-death population models with structurally constrained substitution models.

Evolutionary studies in population genetics and ecology were mainly focused on predicting and understanding past evolutionary events. Recently, however, a growing trend explores the prediction of evolutionary trajectories toward the future promoted by its wide variety of applications. In this context, we introduce a forecasting protein evolution method that integrates birth-death population models with substitution models that consider selection on protein folding stability. In contrast to traditional population genetics methods that usually make the unrealistic assumption of simulating molecular evolution separately from the evolutionary history, the present method combines both processes to simultaneously model forward-in-time birth-death evolutionary trajectories and protein evolution under structurally constrained substitution models that outperformed traditional empirical substitution models. We implemented the method into a freely available computer framework. We evaluated the accuracy of the predictions with several monitored viral proteins of broad interest. Overall, the method showed acceptable errors in predicting the folding stability of the forecasted protein variants, but, expectedly, the errors were larger in the prediction of the corresponding sequences. We conclude that forecasting protein evolution is feasible in certain evolutionary scenarios and provide suggestions to enhance its accuracy by improving the underlying models of evolution.