osprey

Abstract

Summary We have developed a suite of protein redesign algorithms that improves realistic in silico modeling of proteins. These algorithms are based on three characteristics that make them unique: (1) improved flexibility of the protein backbone, protein side chains, and ligand to accurately capture the conformational changes that are induced by mutations to the protein sequence; (2) modeling of proteins and ligands as ensembles of low-energy structures to better approximate binding affinity; and (3) a globally-optimal protein design search, guaranteeing that the computational predictions are optimal with respect to the input model. Here, we illustrate the importance of these three characteristics. We then describe OSPREY, a protein redesign suite that implements our protein design algorithms. OSPREY has been used prospectively, with experimental validation, in several biomedically-relevant settings. We show in detail how OSPREY has been used to predict resistance mutations and explain why improved flexibility, ensembles, and provability are essential for this application.

Enhanced Potency of a Broadly Neutralizing HIV-1 Antibody In Vitro Improves Protection against Lentiviral Infection In Vivo

“…All VRC07-gp120 interface residues of the Ab were considered for mutation. For each amino acid position, a structure-based design was conducted using OSPREY (61,62). The top-ranked OSPREY mutants were visualized for gained interface interactions using Probe (63) and selected for mutagenesis.…”

“…Specific amino acids in the variable heavy-and variable light-framework regions were chosen for reversion to germ line. Structural analysis and structure-based design were performed using OSPREY (61,62), MolProbity (65), and PyMOL (PyMOL Molecular Graphics System, version 1.5.0.4; Schrödinger, LLC).…”

“…Additional mutations to Asp or Glu in the heavy-chain second complementarity determining region (CDR H2) and CDR L1 were introduced to improve biophysical properties (67). Structure-based antibody redesign and mutation scoring was performed using OSPREY (61,62).…”

Recent advances in automated protein design and its future challenges

“…Some models may utilize either small, discrete search around the target backbone topology, using predetermined backbone libraries, or a heuristic search with continuous global backbone movements [106]. …”

“…Making this assumption drastically simplifies the calculation of the unfolded state as a single reference energy can be used for any amino acid (or amino acid triplet), reducing the intractable conformational search problem to a simple lookup table. This is the approach used in most protein design programs [106,155]. However, the structure of the denatured state is known to be not entirely random and persistent structure in the unfolded state in the form of local hydrophobic clusters and residual secondary structure (SS) will reduce the accuracy of the technique [156,157].…”