Highly coordinated water molecules are frequently an integral part of protein-protein and protein-ligand interfaces. We introduce an updated energy model that efficiently captures the energetic effects of these ordered water molecules on the surfaces of proteins. A two-stage method is developed in which polar groups arranged in geometries suitable for water placement are first identified, then a modified Monte Carlo simulation allows highly coordinated waters to be placed on the surface of a protein while simultaneously sampling amino acid side chain orientations. This "semi-explicit" water model is implemented in Rosetta and is suitable for both structure prediction and protein design. We show that our new approach and energy model yield significant improvements in native structure recovery of protein-protein and protein-ligand docking discrimination tests.

We present a method for design problems wherein the goal is to maximize or specify the value of one or more properties of interest (e.g. maximizing the fluorescence of a protein). We assume access to black box, stochastic “oracle" predictive functions, each of which maps from design space to a distribution over properties of interest. Because many state-of-the-art predictive models are known to suffer from pathologies, especially for data far from the training distribution, the problem becomes different from directly optimizing the oracles. Herein, we propose a method to solve this problem that uses model-based adaptive sampling to estimate a distribution over the design space, conditioned on the desired properties.

SUMMARY: A large number of proteins function as homo-oligomers; therefore, predicting homo-oligomeric structure of proteins is of primary importance for understanding protein function at the molecular level. Here, we introduce a web server for prediction of protein homo-oligomer structure. The server takes a protein monomer structure as input and predicts its homo-oligomer structure from oligomer templates selected based on sequence and tertiary/quaternary structure similarity. Using protein model structures as input, the server shows clear improvement over the best methods of CASP9 in predicting oligomeric structures from amino acid sequences. AVAILABILITY: http://galaxy.seoklab.org/gemini. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Protein structures can be reliably predicted by template-based modeling (TBM) when experimental structures of homologous proteins are available. However, it is challenging to obtain structures more accurate than the single best templates by either combining information from multiple templates or by modeling regions that vary among templates or are not covered by any templates. RESULTS: We introduce GalaxyTBM, a new TBM method in which the more reliable core region is modeled first from multiple templates and less reliable, variable local regions, such as loops or termini, are then detected and re-modeled by an ab initio method. This TBM method is based on "Seok-server," which was tested in CASP9 and assessed to be amongst the top TBM servers. The accuracy of the initial core modeling is enhanced by focusing on more conserved regions in the multiple-template selection and multiple sequence alignment stages. Additional improvement is achieved by ab initio modeling of up to 3 unreliable local regions in the fixed framework of the core structure. Overall, GalaxyTBM reproduced the performance of Seok-server, with GalaxyTBM and Seok-server resulting in average GDT-TS of 68.1 and 68.4, respectively, when tested on 68 single-domain CASP9 TBM targets. For application to multi-domain proteins, GalaxyTBM must be combined with domain-splitting methods. CONCLUSION: Application of GalaxyTBM to CASP9 targets demonstrates that accurate protein structure prediction is possible by use of a multiple-template-based approach, and ab initio modeling of variable regions can further enhance the model quality.