Using NMR Chemical Shifts and Cryo-EM Density Restraints in Iterative Rosetta-MD Protein Structure Refinement.

Cryo-EM has become one of the prime methods for protein structure elucidation, frequently yielding density maps with near-atomic or medium resolution. If protein structures cannot be deduced unambiguously from the density maps, computational structure refinement tools are needed to generate protein structural models. We have previously developed an iterative Rosetta-MDFF protocol that used cryo-EM densities to refine protein structures.

Iterative Molecular Dynamics-Rosetta Membrane Protein Structure Refinement Guided by Cryo-EM Densities.

Knowing atomistic details of proteins is essential not only for the understanding of protein function but also for the development of drugs. Experimental methods such as X-ray crystallography, NMR, and cryo-electron microscopy (cryo-EM) are the preferred forms of protein structure determination and have achieved great success over the most recent decades. Computational methods may be an alternative when experimental techniques fail.

Computational methods in drug discovery.

The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development.

Predicting Protein Secondary Structure Using Consensus Data Mining (CDM) Based on Empirical Statistics and Evolutionary Information.

Predicting the secondary structure of a protein from its sequence still remains a challenging problem. The prediction accuracies remain around 80 %, and for very diverse methods. Using evolutionary information and machine learning algorithms in particular has had the most impact.

Fold-specific sequence scoring improves protein sequence matching.

Background: Sequence matching is extremely important for applications throughout biology, particularly for discovering information such as functional and evolutionary relationships, and also for discriminating between unimportant and disease mutants. At present the functions of a large fraction of genes are unknown; improvements in sequence matching will improve gene annotations. Universal amino acid substitution matrices such as Blosum62 are used to measure sequence similarities and to identify distant homologues, regardless of the structure class.

Predicting Designability of Small Proteins from Graph Features of Contact Maps.

Highly designable structures can be distinguished based on certain geometric graphical features of the interactions, confirming the fact that the topology of a protein structure and its residue-residue interaction network are important determinants of its designability. The most designable structures and least designable structures obtained for sets of proteins having the same number of residues are compared. It is shown that the most designable structures predicted by the graph features of the contact diagrams are more densely packed, whereas the poorly designable structures are more open structures or structures that are loosely packed.

Volumes and surface areas: geometries and scaling relationships between coarse- grained and atomic structures.

Computing volumes and surface areas of molecular structures is generally considered to be a solved problem, however, comparisons presented in this review show that different ways of computing surface areas and volumes can yield dramatically different values. Volumes and surface areas are the most basic geometric properties of structures, and estimating these becomes especially important for large scale simulations when individual components are being assembled in protein complexes or drugs being fitted into proteins. Good approximations of volumes and surfaces are derived from Delaunay tessellations, but these values can differ significantly from those from the rolling ball approach of Lee and Richards (3V webserver).

Combining statistical potentials with dynamics-based entropies improves selection from protein decoys and docking poses.

Protein structure prediction and protein-protein docking are important and widely used tools, but methods to confidently evaluate the quality of a predicted structure or binding pose have had limited success. Typically, either knowledge-based or physics-based energy functions are employed to evaluate a set of predicted structures (termed "decoys" in structure prediction and "poses" in docking), with the lowest energy structure being assumed to be the one closest to the native state. While successful for many cases, failures are still common.

Exploration of the relationship between topology and designability of conformations.

Protein structures are evolutionarily more conserved than sequences, and sequences with very low sequence identity frequently share the same fold. This leads to the concept of protein designability. Some folds are more designable and lots of sequences can assume that fold.

Free energies for coarse-grained proteins by integrating multibody statistical contact potentials with entropies from elastic network models.

We propose a novel method of calculation of free energy for coarse grained models of proteins by combining our newly developed multibody potentials with entropies computed from elastic network models of proteins. Multi-body potentials have been of much interest recently because they take into account three dimensional interactions related to residue packing and capture the cooperativity of these interactions in protein structures. Combining four-body non-sequential, four-body sequential and pairwise short range potentials with optimized weights for each term, our coarse-grained potential improved recognition of native structure among misfolded decoys, outperforming all other contact potentials for CASP8 decoy sets and performance comparable to the fully atomic empirical DFIRE potentials.

Multibody coarse-grained potentials for native structure recognition and quality assessment of protein models.

Multibody potentials have been of much interest recently because they take into account three dimensional interactions related to residue packing and capture the cooperativity of these interactions in protein structures. Our goal was to combine long range multibody potentials and short range potentials to improve recognition of native structure among misfolded decoys. We optimized the weights for four-body nonsequential, four-body sequential, and short range potentials to obtain optimal model ranking results for threading and have compared these data against results obtained with other potentials (26 different coarse-grained potentials from the Potentials 'R'Us web server have been used).