Abstract
Mutation protocols are a key tool in computational biophysics for modelling unknown side chain conformations. In particular, these protocols are used to generate the starting structures for molecular dynamics simulations. The accuracy of the initial side chain and backbone placement is crucial to obtain a stable and quickly converging simulation. In this work, we assessed the performance of several mutation protocols in predicting the most probable conformer observed in finite temperature molecular dynamics simulations for a set of protein-peptide crystals differing only by single-point mutations in the peptide sequence. Our results show that several programs which predict well the crystal conformations fail to predict the most probable finite temperature configuration. Methods relying on backbone-dependent rotamer libraries have, in general, a better performance, but even the best protocol fails in predicting approximately 30% of the mutations.
Highlights
IntroductionTo improve the accuracy of the side chain prediction, a fundamental step is to sample the conformations of the system
The results suggest a rational pipeline to improve the mutational protocols for efficient molecular dynamics (MD) simulations, and protein or peptide design
We found that the backbone dihedrals remain quite stable during all the MD trajectories
Summary
To improve the accuracy of the side chain prediction, a fundamental step is to sample the conformations of the system. This can be performed using stochastic methods such as Monte Carlo, based on movements constrained by dihedrals,[16] and classical or enhanced molecular dynamics (MD) simulations.[17] sampling the rotamer space of the amino acid is time consuming. In protein design applications, where iterative single-point mutations protocols are required for designing novel molecules, running long MD simulations for each mutation is computationally expensive because the number of mutations that have to be explored, even for a small peptide, is extremely large.[18] Protocols able to predict rotamers correctly can diminish the required simulation time to explore the conformational space
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