Computational Chemistry and Biology Core Facility

• Dedicated dual quad core server for complex calculations and fault-proof mirrored data storage
• Two additional dual quad core workstations for locally running specialized and computationally expensive simulations
• Four quad core workstations available for use by trained outside personnel to submit simulations to the central server and analyze the resulting output.
• All workstations have access to the full Accelrys Discovery Studio and Tripos Sybyl-X software suites, as well as a wide variety of both commercial and open source scientific software, including ChemBioDraw, Chem3D, Wavefunction Spartan, Hypercube HyperChem, Molegro Virtual Docker, Ligand Scout, Molsoft ICM-Pro, Molecular Discovery VolSurf+, Autodock, AMBER 12, Vega ZZ, HEX Protein Docking, and CBD Field Align.

Determining the structure and properties of a macromolecule, such as enzymes, antibodies, DNA, or RNA, is fundamental to understanding structure-activity relationships, protein-protein interactions, DNA/RNA binding, and small molecule design. The CCB Core utilizes validated scientific tools to aid in every step of macromolecule research. Services include:

• Protein sequence analysis of enzymes, antibodies, and multiple chain proteins
  • Protein sequence alignment
  • Secondary structure prediction
  • Transmembrane segment prediction
  • Phylogenic / evolutionary trace analysis
• 3D structure generation of macromolecules
  • Analysis and cleaning of models from 3D structure databases (PDB, etc.)
  • Construction and evaluation of protein homology models when X-ray/NMR data is unavailable.
  • Antibody loop refinement, loop grafting, or ab initio loop modeling
  • Protein side-chain and loop conformation prediction and optimization
• Predicting macromolecule interactions
  • Protein-protein docking and binding partner/interaction interface prediction
  • DNA/RNA-ligand, protein-ligand, and protein-DNA/RNA interactions
  • Transmembrane protein interaction with lipid membranes
  • Antigen-antibody docking
• Predicting effects of amino acid mutations or modifications on macromolecule properties
  • Structural alterations
  • Impact on binding affinity and protein-protein interactions
  • Effects on protein stability
  • Potential for protein aggregation

The CCB Core can perform sophisticated simulations of the potential interactions between macromolecules, ligands, cofactors, membrane surfaces, and metal ions using advanced molecular mechanics, quantum mechanics, spatial alignments, and energetic calculations. Capabilities include:

• Optimization and minimization of DNA, RNA, carbohydrates, lipids, proteins, peptides, and small molecules
• Explicit or implicit solvent-based molecular mechanics and molecular dynamics simulations using a variety of atomic force fields
• Addition of implicit membranes for refinement of transmembrane or membrane-associated protein structures
• Prediction of protein and amino acid side chain ionization and pK values
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A major goal of the CCB Core is to aid in the discovery and design of novel small molecule drugs by rapidly identifying and refining promising compounds utilizing a variety of strategies, including:

• Evaluation of quantitative structure activity relationships (QSAR) of known and potential drug candidates
• Structure-based and fragment-based design of novel compounds
• Virtual high-throughput screening of small molecule libraries, including all compound libraries available at the High Throughput and High Content Screening (HTS/HCS) Core Facility
• Small molecule conformer generation and docking into flexible receptor binding sites to identify lead compounds
• Predicted binding energy analysis to prioritize early stage screening
• De novo evolution and R-group substitutions of small molecule scaffolds in situ to optimize potency and target specificity
• Generation and validation of qualitative and quantitative pharmacophore models to identify structural characteristics necessary for binding.

The CCB Core can perform early assessment of novel drug candidates by calculating predicted absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties for collections of molecules. The calculated results can be used to eliminate compounds with unfavorable ADMET characteristics and evaluate proposed structural alterations to improve ADMET properties prior to compound synthesis. The services include evaluation and prediction of:

• Aqueous solubility
• Plasma protein binding
• Blood-brain barrier penetration
• CYP2D6 binding
• Human intestinal absorption
• Hepatotoxicity
• Quantitative Structure Toxicity Relationships (QSTR)

The visualization of molecular structures and interactions is an essential aspect of analyzing and communicating the outcomes of modeling studies. Molecular graphics, sequence maps, 2D and 3D graphs, histograms, and heat maps are all viable methods to share the mechanistic insights resulting from computational analyses. The CCB Core specializes in the production of clear, concise, publication-quality graphics for grant submissions, manuscripts, reviews, and presentations. CCB Core personnel also have access to professional 3D modeling and animation software, such as Lightwave 3D, Cinema 4D, Modo, and Zbrush for the production of eye-catching figures, illustrations, animations, and cover art submissions that are not possible using traditional scientific modeling software.​

Authorship

Co-authorship of manuscripts for individuals involved in the modeling studies is generally expected as core personnel typically make significant contributions in the form of intellectual input, experimental design, data analysis/interpretation, and visualization of results. Core personnel will provide figures, figure legends, and manuscript text for the relevant methods, results, and discussion sections pertaining to the modeling studies. Authors should also be given the opportunity to review and edit the manuscript in its final form prior to submission.

In addition, acknowledgment of the CCB Core Facility should also be made in any publications that include data generated utilizing core facilities, resources, and/or software. An example of an appropriate acknowledgment would be: “The authors wish to thank the Computational Chemistry and Biology Core Facility at the University of Colorado Anschutz Medical Campus for their contributions to this manuscript.”

Grant Assistance

The CCB core is happy to provide letters of support, generation of preliminary results, and assistance in the writing of grant submissions. For letters of support, please allow at least 2 weeks from the time of your request for receipt of the letter. Please include the following information in your request: (1) title of the grant, (2) your title and mailing address, (3) agency to which you are submitting the grant and (4) 2-3 sentences on the specific aims and/or goals of the proposal.

For preliminary results and assistance in grant writing, please make your requests as soon as possible as preliminary studies typically have a turnaround of 4-6 weeks. However, more time may be required during periods of high utilization of the core facility (i.e. just prior to grant submission deadlines). Allocation of funds for computational studies and/or core personnel salary support in the grant budget qualifies the PI(s) for a flat rate to produce the necessary preliminary molecular modeling data (see Costs section below for further details). Obtaining grant support for longer-term CCB Core studies is a more cost-effective approach than utilizing the hourly fee-for-service rate structure, particularly if it includes salary support for core personnel.

Training

The CCB Core offers training services for graduate students and postdocs in the use of the facility. A typical training session will last 1-2 hours and generally, 3-4 sessions are required to become proficient in the use of the software. Trained individuals have open access to one of four workstations, pending availability, and may submit jobs to the central server. This can reduce total costs for long-term studies by reducing the amount of time core personnel are required to spend on the project.

Costs

Fee-for-service prices are listed on a per hour basis, with the exception of the preliminary data rate. If the CCB Core Facility is specifically allocated funds in the proposal budget then all the costs associated with the generation of preliminary data, as well as assistance in writing of the proposal, are included in the single flat fee. The extent of the preliminary studies will be agreed upon in advance at the discretion of the CCB Core director. Fee for service estimates of total study costs can be made once the scope of the project is known.