Pair Potentials as Machine Learning Features

Atom pairwise potential functions make up an essential part of many scoring functions for protein decoy detection. With the development of machine learning (ML) tools, there are multiple ways to combine potential functions to create novel ML models and methods. Potential function parameters can be easily extracted; however, it is usually hard to directly obtain the calculated atom pairwise energies from scoring functions. Amber, as one of the most popular suites of modeling programs, has an extensive history and library of force field potential functions. In this work, we directly used the force field parameters in ff94 and ff14SB from Amber and encoded them to calculate atom pairwise energies for different interactions. Two sets of structures (single amino acid set and a dipeptide set) were used to evaluate the performance of our encoded Amber potentials. From the comparison results between energy terms obtained from our encoding and Amber, we find energy difference within ±0.06 kcal/mol for all tested structures. Previously we have shown that the Random Forest (RF) model can help to emphasize more important atom pairwise interactions and ignore insignificant ones [ Pei, J.; Zheng, Z.; Merz, K. M. J. Chem. Inf. Model. 2019, 59, 1919−1929]. Here, as an example of combining ML methods with traditional potential functions, we followed the same work flow to combine the RF models with force field potential functions from Amber. To determine the performance of our RF models with force field potential functions, 224 different protein native-decoy systems were used as our training and testing sets We find that the RF models with ff94 and ff14SB force field parameters outperformed all other scoring functions (RF models with KECSA2, RWplus, DFIRE, dDFIRE, and GOAP) considered in this work for native structure detection, and they performed similarly in detecting the best decoy. Through inclusion of best decoy to decoy comparisons in building our RF models, we were able to generate models that outperformed the score functions tested herein both on accuracy and best decoy detection, again showing the performance and flexibility of our RF models to tackle this problem. Finally, the importance of the RF algorithm and force field parameters were also tested and the comparison results suggest that both the RF algorithm and force field potentials are important with the ML scoring function achieving its best performance only by combining them together. All code and data used in this work are available at https://github.com/JunPei000/FFENCODER_for_Protein_Folding_Pose_Selection .