Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding.

We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking, rigid receptor docking, and protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective and prospective testing succeeded to determine protein-ligand binding modes with a root-mean-square deviation within 2.5 Å in over 90% of cross-docking cases.

IPRO+/-: Computational Protein Design Tool Allowing for Insertions and Deletions.

Insertions and deletions (indels) in protein sequences alter the residue spacing along the polypeptide backbone and consequently open up possibilities for tuning protein function in a way that is inaccessible by amino acid substitution alone. We describe an optimization-based computational protein redesign approach centered around predicting beneficial combinations of indels along with substitutions and also obtain putative substrate-docked structures for these protein variants. This modified algorithmic capability would be of interest for enzyme engineering and broadly inform other protein design tasks.

PoreDesigner for tuning solute selectivity in a robust and highly permeable outer membrane pore.

Monodispersed angstrom-size pores embedded in a suitable matrix are promising for highly selective membrane-based separations. They can provide substantial energy savings in water treatment and small molecule bioseparations. Such pores present as membrane proteins (chiefly aquaporin-based) are commonplace in biological membranes but difficult to implement in synthetic industrial membranes and have modest selectivity without tunable selectivity.

Computational Redesign of Acyl-ACP Thioesterase with Improved Selectivity toward Medium-Chain-Length Fatty Acids.

Enzyme and metabolic engineering offer the potential to develop biocatalysts for converting natural resources into a wide range of chemicals. To broaden the scope of potential products beyond natural metabolites, methods of engineering enzymes to accept alternative substrates and/or perform novel chemistries must be developed. DNA synthesis can create large libraries of enzyme-coding sequences, but most biochemistries lack a simple assay to screen for promising enzyme variants.

The Iterative Protein Redesign and Optimization (IPRO) suite of programs.

Proteins are an important class of biomolecules with applications spanning across biotechnology and medicine. In many cases, native proteins must be redesigned to improve various performance metrics by changing their amino acid sequences. Algorithms can help sharpen protein library design by focusing the library on sequences that optimize computationally accessible proxies.

Methane oxidation by anaerobic archaea for conversion to liquid fuels.

Given the recent increases in natural gas reserves and associated drawbacks of current gas-to-liquids technologies, the development of a bioconversion process to directly convert methane to liquid fuels would generate considerable industrial interest. Several clades of anaerobic methanotrophic archaea (ANME) are capable of performing anaerobic oxidation of methane (AOM). AOM carried out by ANME offers carbon efficiency advantages over aerobic oxidation by conserving the entire carbon flux without losing one out of three carbon atoms to carbon dioxide.

OptZyme: computational enzyme redesign using transition state analogues.

OptZyme is a new computational procedure for designing improved enzymatic activity (i.e., kcat or kcat/KM) with a novel substrate.

Recent advances in computational protein design.

Proteins are the molecules cells primarily rely on for catalysis, recognition, signaling, defense, locomotion, and structural integrity. Engineering proteins for improved function or new applications is a fast-growing segment of biotechnology and biomedicine. Experimental efforts based on the screening of large mutant libraries have led to many successes but they do not provide quantitative design principles and/or insight into the structural features that underpin the desired function.