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.

An important problem in high-throughput protein crystallography is constructing a protein model from an electron-density map. Previous work by some of this paper's authors [1] describes an automated approach to this otherwise time-consuming process. An important step in the previous method requires searching the density map for many small template protein-fragments. This previous approach uses Fourier convolution to quickly match some rotation of the template to the entire density map. This paper proposes an alternate approach that makes use of the spherical-harmonic decomposition of the template and of some region in the density map. This new framework allows us to mask specific regions of the map, enabling a first-pass filter to eliminate a majority of the density map without requiring an expensive rotational search. We show our new template matching method improves accuracy and reduces running time, compared to our previous approach. Protein models constructed using this matching also show significant accuracy improvement.

MOTIVATION: One bottleneck in high-throughput protein crystallography is interpreting an electron-density map, that is, fitting a molecular model to the 3D picture crystallography produces. Previously, we developed ACMI (Automatic Crystallographic Map Interpreter), an algorithm that uses a probabilistic model to infer an accurate protein backbone layout. Here, we use a sampling method known as particle filtering to produce a set of all-atom protein models. We use the output of ACMI to guide the particle filter's sampling, producing an accurate, physically feasible set of structures. RESULTS: We test our algorithm on 10 poor-quality experimental density maps. We show that particle filtering produces accurate all-atom models, resulting in fewer chains, lower sidechain RMS error and reduced R factor, compared to simply placing the best-matching sidechains on ACMI's trace. We show that our approach produces a more accurate model than three leading methods--Textal, Resolve and ARP/WARP--in terms of main chain completeness, sidechain identification and crystallographic R factor. AVAILABILITY: Source code and experimental density maps available at http://ftp.cs.wisc.edu/machine-learning/shavlik-group/programs/acmi/

We describe a part-based object-recognition framework, specialized to mining complex 3D objects from detailed 3D images. Objects are modeled as a collection of parts together with a pairwise potential function. An efficient inference algorithm - based on belief propagation (BP) -finds the optimal layout of parts, given some input image. We introduce AggBP, a message aggregation scheme for BP, in which groups of messages are approximated as a single message. For objects consisting of N parts, we reduce CPU time and memory requirements from O(N2) to O(N). We apply AggBP on synthetic data as well as a real-world task identifying protein fragments in three-dimensional images. These experiments show that our improvements result in minimal loss in accuracy in significantly less time.

X-ray crystallography is currently the most common way protein structures are elucidated. One of the most time-consuming steps in the crystallographic process is interpretation of the electron density map, a task that involves finding patterns in a three-dimensional picture of a protein. This paper describes DEFT (DEFormable Template), an algorithm using pictorial structures to build a flexible protein model from the protein's amino-acid sequence. Matching this pictorial structure into the density map is a way of automating density-map interpretation. Also described are several extensions to the pictorial structure matching algorithm necessary for this automated interpretation. DEFT is tested on a set of density maps ranging from 2 to 4Å resolution, producing root- mean-squared errors ranging from 1.38 to 1.84Å.