The workshop will take place in the Havasu Room on 3rd Floor Building 53 from 8:30 to 16:00 on September 15, 2026

Familiarity with protein crystallography and three-dimensional protein structure is a pre-requisite. This workshop is designed for attendees of the Pittsburgh Diffraction Conference with a solid working knowledge of structural biology.

Overview

This one-day workshop guides participants through the complete structure-based drug discovery computational pipeline, from critically evaluating a raw PDB entry through ensemble docking, using a professional integrated modeling environment for the primary hands-on exercises. The final portion of the day surveys the open-source ecosystem alongside SSRL-developed workflows, equipping attendees to reproduce and extend these pipelines.

The workshop is organized around two major blocks:

Morning–Afternoon: Protein preparation, docking, ligand design concepts, molecular dynamics ensemble generation, and comparative docking analysis using an integrated platform.

Late Afternoon: Survey of free open-source tools covering equivalent functionality and specialized training on the new SSRL-developed virtual compound screening pipeline.

Schedule at a Glance

• 8:30 – 8:50   Welcome, Logistics, Software Orientation & User Portal Registration
• 8:50 – 9:35   Crystal vs. solution; biological assembly
• 9:35 – 10:20   Structure preparation & Druggability tutorial overview
• 10:20 – 10:35   Coffee Break
• 10:35 – 11:15   Binding site definition & docking parameters
• 11:15 – 11:55   Rigid protein docking
• 11:55 – 12:40   Lunch Break
• 12:40 – 13:20   Flexible side chain docking & MD ensemble generation
• 13:20 – 13:50   Structure-guided ligand design concepts & Three-way comparison
• 13:50 – 14:05   Coffee Break
• 14:05 – 15:05   The New SSRL-SMB Virtual Screening Pipeline Demo (BraVE)
• 15:05 – 15:35   SSRL Beamline Capabilities & User Program Presentation
• 15:35 – 16:00   Wrap-up, Q&A and resources

Full Schedule

MORNING SESSION: Protein Structure Preparation & Docking

Module 1 | Protein Structure Fundamentals for Computational Work

• 8:30 – 8:50   Welcome, Logistics, and Software Orientation

Lecture + orientation

Workshop goals, schedule, and ground rules

Software environment walkthrough — interface, key panels, file formats

Brief participant background survey: prior docking experience, target types, software familiarity

SSRL Integration: User portal registration walkthrough

• 8:50 – 9:35   From Crystal to Solution: Understanding What You Actually Have

Lecture + Hands-on

Asymmetric unit vs. biological assembly: why the monomer in the PDB is often not the functional unit

Generating and evaluating the biologically relevant oligomeric state

Crystal contacts vs. physiologically meaningful interfaces — how to tell them apart

Practical exercise: load a PDB entry, generate the biological unit, identify crystal packing artifacts

Discussion: implications of oligomeric state for drug binding site accessibility and shape

• 9:35 – 10:20   Cleaning Up Reality: Structure Preparation

Lecture + Hands-on

Alternate conformations: structural meaning and strategies for selection

Missing residues and loops: causes, consequences, and remediation

Missing side chains: rotamer placement and local energy minimization

Structural waters: which to retain, which to remove

Protonation states at physiological pH: histidine tautomers, Asp/Glu, Lys/Arg, metal coordination

Practical exercise: take a 'messy' real-world PDB entry through a complete preparation pipeline

SSRL Integration: Introduction to open-source methods to locate binding pockets and evaluate if a protein is likely druggable to justify a fragment screening campaign

• 10:20 – 10:35   Coffee Break

• 10:35 – 11:15   Defining the Binding Site and Setting Docking Parameters

Lecture + Hands-on

Binding site identification: known active sites vs. cryptic and allosteric pockets

Site characterization: volume, hydrophobicity, electrostatics, druggability scoring

Setting the docking search space: size, center, and padding considerations

Scoring function overview: what the numbers mean and what they do not

Ligand preparation: protonation states, tautomers, conformer generation, charge assignment

Practical exercise: define a docking site on a prepared target and configure all run parameters

Module 2 | Docking: From Rigid to Flexible

• 11:15 – 11:55   Rigid Protein Docking

Lecture + Hands-on

Rationale for rigid receptor docking: speed, reproducibility, interpretability

Docking a reference ligand and a small analog set into the prepared PDB structure

Analyzing and ranking poses: scoring metrics, visual inspection, key interaction fingerprints

Practical exercise: redock the co-crystallized ligand and evaluate pose quality vs. crystal geometry

• 11:55 – 12:40   Lunch Break

AFTERNOON SESSION: Flexible Docking, Ligand Design & Ensemble Methods

• 12:40 – 13:20   Flexible Side Chain Docking & Ensemble Generation

Lecture + Hands-on

Induced fit concepts: receptor flexibility beyond the rigid approximation

Selecting which side chains to treat as flexible: proximity, alternate conformations, known mobility

Computational cost vs. accuracy tradeoffs, practical guidance on scope

Practical exercise: repeat the rigid docking run with flexible side chains; compare poses and scores

Discussion: why a single crystal structure is a snapshot and the case for conformational ensembles

Core workflow: local pocket breathing, setup parameters, and extracting 3–5 diverse snapshot conformers

Module 3 | Structure-Guided Ligand Design Concepts & Comparative Analysis

• 13:20 – 13:50   Ligand Design Informed by the Binding Site & Three-Way Comparison

Guided analysis and lecture-focused demonstration

Reading the binding site: hydrogen bond donors and acceptors, hydrophobic pockets, metal centers

Fragment growing, linking, and merging strategies

Bioisostere replacement guided by structural context

Side-by-side evaluation of the three docking strategies:

•   Condition A - PDB structure with rigid receptor docking
•   Condition B - PDB structure with flexible side chain docking
•   Condition C - MD ensemble with rigid receptor docking on each conformer

Interpreting disagreements and matching the approach to project constraints

• 13:50 – 14:05   Coffee Break

LATE AFTERNOON SESSION: SSRL Pipelines and Infrastructure

Module 4 | The SSRL-SMB Virtual Compound Screening Pipeline

• 14:05 – 15:05   The New SSRL-SMB Virtual Screening Pipeline (BraVE)

Lecture + interactive software demonstration + discussion

Pipeline Release: Introduction and user community training on the new BraVE-funded, SSRL-developed pipeline available for SSRL SMB users.

Workflow Walkthrough: Step-by-step demonstration of how to run the "SSRL-SMB virtual compound screening pipeline", describing its underlying open-source components and how to understand the output data

Fragment & Small Molecule Support: Utilizing the pipeline to locate potential smaller fragment-like or larger compounds to supplement standard experimental fragment libraries during initial crystallography-based screening runs

Predictive Optimization: Applying initial experimental screening results to improve future predictions of larger drug-like compounds, featuring a practical screening example against a database of known FDA tested/approved drugs/compounds