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The application of hierarchical optimization of protein potential-energy landscapes to optimize the UNRES force field using multiple training proteins is reported. The resulting force field trained on a set of four proteins gives good medium-resolution predictions of the structures of most of the alpha- and the alpha + beta-proteins, but still could not handle nontrivial beta-motifs sufficiently well.

The application of the proposed method of hierarchical optimization of the protein energy landscape to optimize the off-lattice united-residue (UNRES) force field using single training proteins is presented. Technical details of the method, including the maintenance of proper secondary structure and a method to classify structure, are described.

The development of proposed method for optimizing potential-energy functions for protein-structure prediction and folding simulations aimed at obtaining hierarchical energy landscapes of the protein chosen to calibrate a force field is presented. The structure of each benchmark protein is described in terms of structural levels, the number of native structural elements increasing in a given order with level number.

Multibody terms pertaining to the correlation between electrostatic interaction in the UNRES force field were reparameterized on relevant model systems. The resultant force field predicted the structures of proteins with alpha and beta structure.

The N-terminal cysteine-rich somatomedin B (SMB) domain of the human glycoprotien vitronectin contains the high-affinity binding sites for plasminogen activator inhibitor-1(PAI-1) and the urokinase receptor (uPAR). The studies demonstrate that the three dimensional structure of the SMB domain is extremely compact and that the disulfide bonds are packed in the center of the domain forming a covalently bonded core.

Deconjugation of ubiquitin from cellular proteins is catalyzed by the deubiquitin hydrolase (DUB) family of enzymes and is an important component of the ubiquitin regulatory system affecting cellular function beyond maintenance of monomeric pools of ubiquitin. UCH-L3 efficiently cleaves small C-terminal amides of ubiquitin.

Calculations of the diabatic energy surfaces of terminally-blocked amino-acid residues were performed at the Moller-Plesset (MP2) ab initio level of theory with the 6-31G(d,p) basis set. It is essential to have high quality potential-energy surfaces to parametrize a coarse-grain force field, and errors in the parent single-residue all-atom energy surfaces propagate to the mean-field surfaces by numerical integration.

A method for optimizing potential-energy functions of proteins is proposed. The method assumes a hierarchical structure of the energy landscape, which means that the energy decreases as the number of native-like elements in a structure increases, being lowest for structures from the native family and highest for structures with no native-like element. A level of the hierarchy is defined as a family of structures with the same number of native-like elements (or degree of native likeness). Optimization of a potential-energy function is aimed at achieving such a hierarchical structure of the energy landscape by forcing appropriate free-energy gaps between hierarchy levels to place their energies in ascending order. This procedure is different from methods developed thus far, in which the energy gap and/or the Z score between the native structure and all non-native structures are maximized, regardless of the degree of native likeness of the non-native structures. The advantage of this approach lies in reducing the number of structures with decreasing energy, which should ensure the searchability of the potential. The method was tested on two proteins, PDB ID codes 1FSD and 1IGD, with an off-lattice united-residue force field. For 1FSD, the search of the conformational space with the use of the conformational space annealing method and the newly optimized potential-energy function found the native structure very quickly, as opposed to the potential-energy functions obtained by former optimization methods. After even incomplete optimization, the force field obtained by using 1IGD located the native-like structures of two peptides, 1FSD and betanova (a designed three-stranded [beta]-sheet peptide), as the lowest-energy conformations, whereas for the 46-residue N-terminal fragment of staphylococcal protein A, the native-like conformation was the second-lowest-energy conformation and had an energy 2 kcal/mol above that of the lowest-energy structure.

Three energy functions were developed to simulate the free energy of proteins from the alpha, beta and alpha/beta structural classes is presented. The study finally uses a simple model system to show that the VMC protocol does not require exhaustive sampling of medium- and high-energy structures in order to optimize the parameters of the potential energy adequately.

The CAS MCSCF/CAS MCQDPT2 ab initio method utilizing the 6-31G* basis set was used to study the 1,4-cycloaddition reactions of singlet oxygen with s-cis-1,3-butadiene to form 3,6-dihydrol[1,2]dioxin and to benzene to form 2,3-dioxabicyclo-[2.2.2]octa-5,7-diene.

The potentials of mean force (PMFs) are determined for systems that have involved the formation of nonpolar dimers composed of methane, ethane, propane, isobutane and neopentane, respectively, in water, by using the TIP3P water model and in vacuo. It is shown that the neopentane dimer is too small to be treated as a macroscopic hydrophobic object.

Study is presented on the modification and parametrization of the united-residue (UNRES) force field for energy-based protein structure prediction and protein folding simulations. Result demonstrates that it is possible to optimize the UNRES force field for canonical simulations using a protein of any type of secondary structure.

Recent improvements of a hierarchical ab initio or de novo approach for predicting both [Alpha] and [Beta] structures of proteins are described. The united-residue energy function used in this procedure includes multibody interactions from a cumulant expansion of the free energy of polypeptide chains, with their relative weights determined by Z-score optimization. The critical initial stage of the hierarchical procedure involves a search of conformational space by the conformational space annealing (CSA) method, followed by optimization of an all-atom model. The procedure was assessed in a recent blind test of protein structure prediction (CASP4). The resulting lowest-energy structures of the target proteins (ranging in size from 70 to 244 residues) agreed with the experimental structures in many respects. The entire experimental structure of a cyclic [Alpha]-helical protein of 70 residues was predicted to within 4.3 [Angstrom] [Alpha]-carbon ([C.sup.[Alpha]]) rms deviation (rmsd) whereas, for other [Alpha]-helical proteins, fragments of roughly 60 residues were predicted to within 6.0 [Angstrom] [C.sup.[Alpha]] rmsd. Whereas [Beta] structures can now be predicted with the new procedure, the success rate for [Alpha]/[Beta]- and [Beta]-proteins is lower than that for [Alpha]-proteins at present. For the [Beta] portions of [Alpha]/[Beta] structures, the [C.sup.[Alpha]] rmsd's are less than 6.0 [Angstrom] for contiguous fragments of 30-40 residues; for one target, three fragments (of length 10, 23, and 28 residues, respectively) formed a compact part of the tertiary structure with a [C.sup.[Alpha]] rmsd less than 6.0 [Angstrom]. Overall, these results constitute an important step toward the ab initio prediction of protein structure solely from the amino acid sequence.