Learning Path: Oligonucleotide Modeling
Nucleic acids have recently become both promising therapeutics and intriguing drug targets. Their flexibility and strongly-charged backbone can push computational approaches made for protein targets to their limits. This learning path provides an overview of Schrödinger tools applicable to nucleic acids.
PublicationAccurate Physics-Based Prediction of Binding Affinities of RNA- and DNA-Targeting LigandsThe OPLS 4 force field is fully parametrized for nucleic acids (including charges, torsions, and sugar puckering). Also see this publication's supporting information for additional details.
Structure Building and Preparation
DocumentationMM-GBSA residue scanning for mutating nucleic acidsCall the backend from the command line as
$SCHRODINGER/run -FROM psp mut_pred.py <jobname>.maegz -dna_muts_file dna_muts.txt -dist 5 -forcefield OPLS4 and visualize the results using the Residue Scanning Viewer panel in Maestro.
DocumentationAdding custom selection sets
Structure and interaction analysis
TutorialUnderstanding and Visualizing Target FlexibilityWhile this tutorial uses a protein target, the methods it shows are also applicable to nucleic acids.
TutorialIntroduction to All-Atom Molecular Dynamics Simulations with DesmondWhile this tutorial uses a protein target, MD setup for nucleic acids works similarly. Adding salt and appropriate counterions is essential for nucleic acids.
TutorialIntroduction to MD Trajectory Analysis with DesmondMost standard Trajectory Player analyses work for RNA/DNA.
Commandanalyze_trajectory_ppi.pyscript can be used to analyze interactions for user-specified atom sets. Call as
$SCHRODINGER/run analyze_trajectory_ppi.py <md_job>-out.cms <md_job_out>.csv 'nucleic_acids' 'not nucleic_acids'
Documentationtrajectory_RNA_analysisscript calculates all nucleic acid torsions, sugar puckering, phase and amplitude, and base pair interactions. It is currently not included in the Schrödinger software release, however it is available upon request.
DocumentationProtein Interaction Analysis panelCompatible with interaction studies of nucleic acids with both protein or another nucleic acid.
DocumentationMultiple Sequence ViewerWorks for standard nucleic acid residues. Non-standard residues are labeled N or X.
Do you work with nucleic acids as ligands or targets?
VideoComputational strategies for discovering and optimizing RNA- and DNA-targeting moleculesThis webinar provides a comprehensive overview of computational solutions for working with nucleic acid targets.
Binding site identification
TutorialAnalyzing Binding Sites of Nucleic Acids with SiteMapThe scoring function in SiteMap has been recalibrated for improved RNA support. See this publication for details.
TutorialExploring Protein Binding Sites with Mixed-Solvent Molecular DynamicsMxMD works for nucleic acids, but has not been extensively validated.
Virtual screening for nucleic acid receptors
The following receptor-based stages of the Schrödinger virtual screening pipeline have been augmented and validated for use on nucleic acid targets. Glide WS uses WaterMap, whose application to DNA/RNA systems is under active development at the moment.
TutorialSmall Molecule – Oligonucleotide Docking with GlideGlide contains a variant of its scoring function optimized for RNA receptors.
PublicationEnabling in-silico Hit Discovery Workflows Targeting RNA with Small MoleculesPublication describing our work on validating virtual screening methods for nucleic acid targets, including the RNA-specific adjustments to SiteMap's and Glide's scoring functions.
TutorialRe-scoring Docked Ligands with MM-GBSAWhile this tutorial uses a protein target as example, Prime MM-GBSA can be applied to nucleic acids. There has been limited validation for the results.
Lead optimization techniques for nucleic acid targets
TutorialForming RNA – Ligand Interactions with Ligand DesignerPose and property based design of DNA/RNA-binding small molecules.
PublicationAccurate Physics-Based Prediction of Binding Affinities of RNA- and DNA-Targeting LigandsPublication containing the results of our retrospective validation of FEP+ on nucleic acid targets.
Docking nucleic acids to proteins
DocumentationDocking with PIPERIn standard mode, docking nucleic acids with proteins is possible but has limited validation.
Conclusion and Next Steps
This concludes the overview of Schrödinger tools and workflows which have been validated for use on or with nucleic acid targets. For more in-depth guidance on particular scientific workflows, consult our other learning resources.
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