OpenFold: retraining AlphaFold2 yields new insights into its learning mechanisms and capacity for generalization.

AlphaFold2 revolutionized structural biology with the ability to predict protein structures with exceptionally high accuracy. Its implementation, however, lacks the code and data required to train new models. These are necessary to (1) tackle new tasks, like protein-ligand complex structure prediction, (2) investigate the process by which the model learns and (3) assess the model's capacity to generalize to unseen regions of fold space.

Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus.

Antimicrobial resistance presents a significant health care crisis. The mutation F98Y in Staphylococcus aureus dihydrofolate reductase (SaDHFR) confers resistance to the clinically important antifolate trimethoprim (TMP). Propargyl-linked antifolates (PLAs), next generation DHFR inhibitors, are much more resilient than TMP against this F98Y variant, yet this F98Y substitution still reduces efficacy of these agents.

Novel, provable algorithms for efficient ensemble-based computational protein design and their application to the redesign of the c-Raf-RBD:KRas protein-protein interface.

The K* algorithm provably approximates partition functions for a set of states (e.g., protein, ligand, and protein-ligand complex) to a user-specified accuracy ε.

Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant .

The spread of plasmid borne resistance enzymes in clinical isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-conferring isoforms. Using a structure-based approach, we have developed a novel class of ionized nonclassical antifolates (INCAs) that capture the molecular interactions that have been exclusive to classical antifolates.

OSPREY 3.0: Open-source protein redesign for you, with powerful new features.

We present osprey 3.0, a new and greatly improved release of the osprey protein design software. Osprey 3.

BBK* (Branch and Bound Over K*): A Provable and Efficient Ensemble-Based Protein Design Algorithm to Optimize Stability and Binding Affinity Over Large Sequence Spaces.

Computational protein design (CPD) algorithms that compute binding affinity, K, search for sequences with an energetically favorable free energy of binding. Recent work shows that three principles improve the biological accuracy of CPD: ensemble-based design, continuous flexibility of backbone and side-chain conformations, and provable guarantees of accuracy with respect to the input. However, previous methods that use all three design principles are single-sequence (SS) algorithms, which are very costly: linear in the number of sequences and thus exponential in the number of simultaneously mutable residues.

OSPREY Predicts Resistance Mutations Using Positive and Negative Computational Protein Design.

Drug resistance in protein targets is an increasingly common phenomenon that reduces the efficacy of both existing and new antibiotics. However, knowledge of future resistance mutations during pre-clinical phases of drug development would enable the design of novel antibiotics that are robust against not only known resistant mutants, but also against those that have not yet been clinically observed. Computational structure-based protein design (CSPD) is a transformative field that enables the prediction of protein sequences with desired biochemical properties such as binding affinity and specificity to a target.