Prime

Prime is a fully-integrated protein structure prediction solution developed by Schrödinger, designed for life science researchers who need accurate and detailed protein models for drug discovery and related applications. It combines homology modeling and fold recognition into a single, cohesive platform, making it suitable for both experienced computational scientists and those newer to structure-based research.

Prime features an intuitive step-by-step interface that guides users through the entire workflow of structure prediction, providing helpful default settings at each stage of the process. This streamlined approach enables researchers to move efficiently from sequence to high-quality structural model, supporting a wide range of downstream simulations and analyses.

Key Capabilities

• Experimental structure refinement: Refine protein structures obtained through X-ray crystallography, NMR, or Cryo-EM to generate accurate and detailed starting points for subsequent simulations.
• Protein structure prediction from sequence: Accurately predict protein structures from sequence alone to obtain a high-quality model when an experimental structure is not available.
• Side chain prediction and refinement: Predict and refine side chain positions to create a complete, all-atom protein model.
• Macrocycle membrane permeability and conformations: Predict membrane permeability and conformational properties of macrocycles.
• MM-GBSA energetics calculations: Rapidly calculate the energetics of a system of interest using the MM-GBSA method.
• Backbone modeling for low-identity sequences: Create backbone models for early structural investigations or functional annotation in cases of low- or no-sequence identity.
• Protein mutation scanning: Rapidly scan thousands of protein mutations, with tight integration to FEP+ for accurate and thorough screening cascades supporting protein optimization.

Supported Workflows and Applications

• Antibody structure prediction, visualization, quality analysis, and refinement, including antibody humanization guided by computational modeling.
• Generation and scoring of ternary complex structures to enable rational design of targeted protein degraders (PROTACs) and linker optimization.
• Refinement of crystallographic protein-ligand structures using GlideXtal and Phenix/OPLS.
• Re-scoring of docked ligands with MM-GBSA to optimize binding poses and evaluate virtual screening results.
• Approximating protein flexibility without molecular dynamics, including side chain conformational changes and loop refinement.
• Disulfide bond engineering via cysteine scanning to improve thermal stability and facilitate crystallization.
• Drug development workflows involving macrocycles, including sampling, docking, and lead optimization.
• Prediction of small molecule membrane permeability.
• Covalent docking for virtual screening and pose prediction using predefined or custom reaction chemistry.
• Structure-based methods for modeling and optimizing enzymes using rational design approaches.
• Enabling cryo-EM structures for drug discovery to support rational optimization of molecular properties.

Related Products and Integrations

• IFD-MD: Accurate ligand binding mode prediction for novel chemical matter, applicable to on-targets and off-targets.
• FEP+: High-performance free energy calculations for drug discovery, tightly integrated with Prime for protein mutation screening cascades.
• Membrane Permeability: A physics-based solution for rapid and accurate prediction of passive membrane permeability.
• PrimeX: A comprehensive package for accurate protein crystal structure refinement.

Prime is part of the broader Schrödinger computational suite and is supported by extensive documentation, tutorials, online certification courses, and dedicated technical support. Resources include quick start guides, videos, and self-paced molecular modeling courses with access to Schrödinger software, enabling researchers to deploy Prime effectively across a wide range of life science research projects.