Abstract
BackgroundMolecular simulations are used to provide insight into protein structure and dynamics, and have the potential to provide important context when predicting the impact of sequence variation on protein function. In addition to understanding molecular mechanisms and interactions on the atomic scale, translational applications of those approaches include drug screening, development of novel molecular therapies, and targeted treatment planning. Supporting the continued development of these applications, we have developed the SNP2SIM workflow that generates reproducible molecular dynamics and molecular docking simulations for downstream functional variant analysis. The Python workflow utilizes molecular dynamics software (NAMD (Phillips et al., J Comput Chem 26(16):1781-802, 2005), VMD (Humphrey et al., J Mol Graph 14(1):33-8, 27-8, 1996)) to generate variant specific scaffolds for simulated small molecule docking (AutoDock Vina (Trott and Olson, J Comput Chem 31(2):455-61, 2010)).ResultsSNP2SIM is composed of three independent modules that can be used sequentially to generate the variant scaffolds of missense protein variants from the wildtype protein structure. The workflow first generates the mutant structure and configuration files required to execute molecular dynamics simulations of solvated protein variant structures. The resulting trajectories are clustered based on the structural diversity of residues involved in ligand binding to produce one or more variant scaffolds of the protein structure. Finally, these unique structural conformations are bound to small molecule ligand libraries to predict variant induced changes to drug binding relative to the wildtype protein structure.ConclusionsSNP2SIM provides a platform to apply molecular simulation based functional analysis of sequence variation in the protein targets of small molecule therapies. In addition to simplifying the simulation of variant specific drug interactions, the workflow enables large scale computational mutagenesis by controlling the parameterization of molecular simulations across multiple users or distributed computing infrastructures. This enables the parallelization of the computationally intensive molecular simulations to be aggregated for downstream functional analysis, and facilitates comparing various simulation options, such as the specific residues used to define structural variant clusters. The Python scripts that implement the SNP2SIM workflow are available (SNP2SIM Repository. https://github.com/mccoymd/SNP2SIM, Accessed 2019 February ), and individual SNP2SIM modules are available as apps on the Seven Bridges Cancer Genomics Cloud (Lau et al., Cancer Res 77(21):e3-e6, 2017; Cancer Genomics Cloud [www.cancergenomicscloud.org; Accessed 2018 November]).
Highlights
Molecular simulations are used to provide insight into protein structure and dynamics, and have the potential to provide important context when predicting the impact of sequence variation on protein function
Starting with only a PDB formatted file of the protein structure, three independently run functional modules perform the molecular dynamics simulation of a protein variant, cluster of the resulting trajectories based on conformational variation in user defined binding residues, and dock small molecule ligands into each variant specific structural scaffolds
To understand how these molecules may differentially bind to variants of programmed death ligand 1 (PD-L1), known mutations in the binding domain were processed through the SNP2SIM workflow
Summary
The immunomodulatory protein programmed death ligand 1 (PD-L1) was used to demonstrate a typical application of the SNP2SIM workflow to drug development in immunotherapy. By simulating the variant specific contributions to the overall protein conformational dynamics and ligand binding, the unique impact of a variant can be quantified even when the mutated residues do not occur at the interaction interface. This offers an advantage over using the crystal structure as the basis for small molecule docking simulations, instead providing a set of structures that is specific to the impact of the given variant. Even for the wildtype structure, two populated conformations were identified which show slightly modified geometries of the protein backbone found in the crystal structure
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