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Side-chain Conformations (side-chain + conformation)
Selected AbstractsLeucine Side-Chain Conformation and Dynamics in Proteins from 13C NMR Chemical ShiftsCHEMBIOCHEM, Issue 9 2009Frans A. A. Mulder Dr. Abstract Look to the left: The carbon nucleus of a substituent in the gauche position about a subtending dihedral angle experiences an NMR chemical shift of about 5 ppm relative to the same chemical group present in the trans position. We demonstrate that this ",-gauche effect" can be utilized to determine the conformation and extent of rotameric averaging for leucine amino acid side chains in the protein calbindin D9k. The success of this approach suggests that rules can be established to define the orientation of other side chains in proteins as well, offering an easy gauge of protein side-chain flexibility, as well as avenues to advance protein structure determination by using side-chain chemical shifts. [source] Connectivity and binding-site recognition: Applications relevant to drug designJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 15 2010Christopher J. R. Illingworth Abstract Here, we describe a family of methods based on residue,residue connectivity for characterizing binding sites and apply variants of the method to various types of protein,ligand complexes including proteases, allosteric-binding sites, correctly and incorrectly docked poses, and inhibitors of protein,protein interactions. Residues within ligand-binding sites have about 25% more contact neighbors than surface residues in general; high-connectivity residues are found in contact with the ligand in 84% of all complexes studied. In addition, a k-means algorithm was developed that may be useful for identifying potential binding sites with no obvious geometric or connectivity features. The analysis was primarily carried out on 61 protein,ligand structures from the MEROPS protease database, 250 protein,ligand structures from the PDBSelect (25%), and 30 protein,protein complexes. Analysis of four proteases with crystal structures for multiple bound ligands has shown that residues with high connectivity tend to have less variable side-chain conformation. The relevance to drug design is discussed in terms of identifying allosteric-binding sites, distinguishing between alternative docked poses and designing protein interface inhibitors. Taken together, this data indicate that residue,residue connectivity is highly relevant to medicinal chemistry. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Synthesis and structural characteristics of lithocholate triads: steroid-type channels occupied by spacer fragmentsACTA CRYSTALLOGRAPHICA SECTION B, Issue 3 2008Urszula Rychlewska Reported in this paper are the syntheses and X-ray investigations of C2 symmetrical molecular A,B,A triads consisting of two steroid units (lithocholic acid or its methyl ester) joined together by linkers derived from bifunctional molecules such as terephthalic acid or N,N,-dicarboxypiperazine. Unlike their monomeric analogues, some of these compounds form inclusion complexes. All steroidal triads form crystals that are highly pseudo-centrosymmetric, in which the constituting molecules are held together either exclusively by van der Waals forces or form lattice inclusion complexes, with guest molecules hydrogen bonded to the host. The presence of carboxyl groups promotes the inclusion of pyridine molecules and the formation of the well known carboxylic acid...pyridine hydrogen bonds. Combined with pairwise face-to-face ,-stacking between pyridine rings, these hydrogen-bond interactions lead to the formation of extended supramolecular tapes, analogous to polymers. The co-crystals of pyridine and a lithocholic acid triad undergo a symmetry-lowering phase transition from a P1 cell with Z = 1 to a P1 cell with Z = 2. The two structures are virtually the same, the two independent molecules in the larger cell being related by pseudo-translation. Changes in the type of spacer between two methyl lithocholate units from planar aromatic (terephthalic acid) to highly puckered aliphatic six-membered ring (N,N,-dicarboxypiperazine) bring about inclusion properties and changes in side-chain conformation in a crystal. Although the efficient packing of these highly elongated molecules is hindered, as indicated by low values of crystal density, ranging from 1.16 to 1.19,g,cm,3, several very short C...O and H...H contacts are present in the crystals. [source] An efficient algorithm for multistate protein design based on FASTERJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 5 2010Benjamin D. Allen Abstract Most of the methods that have been developed for computational protein design involve the selection of side-chain conformations in the context of a single, fixed main-chain structure. In contrast, multistate design (MSD) methods allow sequence selection to be driven by the energetic contributions of multiple structural or chemical states simultaneously. This methodology is expected to be useful when the design target is an ensemble of related states rather than a single structure, or when a protein sequence must assume several distinct conformations to function. MSD can also be used with explicit negative design to suggest sequences with altered structural, binding, or catalytic specificity. We report implementation details of an efficient multistate design optimization algorithm based on FASTER (MSD-FASTER). We subjected the algorithm to a battery of computational tests and found it to be generally applicable to various multistate design problems; designs with a large number of states and many designed positions are completely feasible. A direct comparison of MSD-FASTER and multistate design Monte Carlo indicated that MSD-FASTER discovers low-energy sequences much more consistently. MSD-FASTER likely performs better because amino acid substitutions are chosen on an energetic basis rather than randomly, and because multiple substitutions are applied together. Through its greater efficiency, MSD-FASTER should allow protein designers to test experimentally better-scoring sequences, and thus accelerate progress in the development of improved scoring functions and models for computational protein design. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] The SAAP force field: Development of the single amino acid potentials for 20 proteinogenic amino acids and Monte Carlo molecular simulation for short peptides,JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 13 2009Michio Iwaoka Abstract Molecular simulation by using force field parameters has been widely applied in the fields of peptide and protein research for various purposes. We recently proposed a new all-atom protein force field, called the SAAP force field, which utilizes single amino acid potentials (SAAPs) as the fundamental elements. In this article, whole sets of the SAAP force field parameters in vacuo, in ether, and in water have been developed by ab initio calculation for all 20 proteinogenic amino acids and applied to Monte Carlo molecular simulation for two short peptides. The side-chain separation approximation method was employed to obtain the SAAP parameters for the amino acids with a long side chain. Monte Carlo simulation for Met-enkephalin (CHO-Tyr-Gly-Gly-Phe-Met-NH2) by using the SAAP force field revealed that the conformation in vacuo is mainly controlled by strong electrostatic interactions between the amino acid residues, while the SAAPs and the interamino acid Lennard-Jones potentials are predominant in water. In ether, the conformation would be determined by the combination of the three components. On the other hand, the SAAP simulation for chignolin (H-Gly-Tyr-Asp-Pro-Glu-Thr-Gly-Thr-Trp-Gly-OH) reasonably reproduced a native-like ,-hairpin structure in water although the C-terminal and side-chain conformations were different from the native ones. It was suggested that the SAAP force field is a useful tool for analyzing conformations of polypeptides in terms of intrinsic conformational propensities of the single amino acid units. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009 [source] The minimized dead-end elimination criterion and its application to protein redesign in a hybrid scoring and search algorithm for computing partition functions over molecular ensemblesJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 10 2008Ivelin Georgiev Abstract One of the main challenges for protein redesign is the efficient evaluation of a combinatorial number of candidate structures. The modeling of protein flexibility, typically by using a rotamer library of commonly-observed low-energy side-chain conformations, further increases the complexity of the redesign problem. A dominant algorithm for protein redesign is dead-end elimination (DEE), which prunes the majority of candidate conformations by eliminating rigid rotamers that provably are not part of the global minimum energy conformation (GMEC). The identified GMEC consists of rigid rotamers (i.e., rotamers that have not been energy-minimized) and is thus referred to as the rigid-GMEC. As a postprocessing step, the conformations that survive DEE may be energy-minimized. When energy minimization is performed after pruning with DEE, the combined protein design process becomes heuristic, and is no longer provably accurate: a conformation that is pruned using rigid-rotamer energies may subsequently minimize to a lower energy than the rigid-GMEC. That is, the rigid-GMEC and the conformation with the lowest energy among all energy-minimized conformations (the minimized-GMEC) are likely to be different. While the traditional DEE algorithm succeeds in not pruning rotamers that are part of the rigid-GMEC, it makes no guarantees regarding the identification of the minimized-GMEC. In this paper we derive a novel, provable, and efficient DEE-like algorithm, called minimized-DEE (MinDEE), that guarantees that rotamers belonging to the minimized-GMEC will not be pruned, while still pruning a combinatorial number of conformations. We show that MinDEE is useful not only in identifying the minimized-GMEC, but also as a filter in an ensemble-based scoring and search algorithm for protein redesign that exploits energy-minimized conformations. We compare our results both to our previous computational predictions of protein designs and to biological activity assays of predicted protein mutants. Our provable and efficient minimized-DEE algorithm is applicable in protein redesign, protein-ligand binding prediction, and computer-aided drug design. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] Induced-fit or preexisting equilibrium dynamics?PROTEIN SCIENCE, Issue 4 2008Lessons from protein crystallography, MD simulations on acetylcholinesterase, implications for structure-based drug design Abstract Crystal structures of acetylcholinesterase complexed with ligands are compared with side-chain conformations accessed by native acetylcholinesterase in molecular dynamics (MD) simulations. Several crystallographic conformations of a key residue in a specific binding site are accessed in a simulation of native acetylcholinesterase, although not seen in rotomer plots. Conformational changes upon ligand binding thus involve preexisting equilibrium dynamics. Consequently, rational drug design could benefit significantly from conformations monitored by MD simulations of native targets. [source] Configurational-bias sampling technique for predicting side-chain conformations in proteinsPROTEIN SCIENCE, Issue 9 2006Tushar Jain Abstract Prediction of side-chain conformations is an important component of several biological modeling applications. In this work, we have developed and tested an advanced Monte Carlo sampling strategy for predicting side-chain conformations. Our method is based on a cooperative rearrangement of atoms that belong to a group of neighboring side-chains. This rearrangement is accomplished by deleting groups of atoms from the side-chains in a particular region, and regrowing them with the generation of trial positions that depends on both a rotamer library and a molecular mechanics potential function. This method allows us to incorporate flexibility about the rotamers in the library and explore phase space in a continuous fashion about the primary rotamers. We have tested our algorithm on a set of 76 proteins using the all-atom AMBER99 force field and electrostatics that are governed by a distance-dependent dielectric function. When the tolerance for correct prediction of the dihedral angles is a <20° deviation from the native state, our prediction accuracies for ,1 are 83.3% and for ,1 and ,2 are 65.4%. The accuracies of our predictions are comparable to the best results in the literature that often used Hamiltonians that have been specifically optimized for side-chain packing. We believe that the continuous exploration of phase space enables our method to overcome limitations inherent with using discrete rotamers as trials. [source] Protein,protein docking with multiple residue conformations and residue substitutionsPROTEIN SCIENCE, Issue 6 2002David M. Lorber Abstract The protein docking problem has two major aspects: sampling conformations and orientations, and scoring them for fit. To investigate the extent to which the protein docking problem may be attributed to the sampling of ligand side-chain conformations, multiple conformations of multiple residues were calculated for the uncomplexed (unbound) structures of protein ligands. These ligand conformations were docked into both the complexed (bound) and unbound conformations of the cognate receptors, and their energies were evaluated using an atomistic potential function. The following questions were considered: (1) does the ensemble of precalculated ligand conformations contain a structure similar to the bound form of the ligand? (2) Can the large number of conformations that are calculated be efficiently docked into the receptors? (3) Can near-native complexes be distinguished from non-native complexes? Results from seven test systems suggest that the precalculated ensembles do include side-chain conformations similar to those adopted in the experimental complexes. By assuming additivity among the side chains, the ensemble can be docked in less than 12 h on a desktop computer. These multiconformer dockings produce near-native complexes and also non-native complexes. When docked against the bound conformations of the receptors, the near-native complexes of the unbound ligand were always distinguishable from the non-native complexes. When docked against the unbound conformations of the receptors, the near-native dockings could usually, but not always, be distinguished from the non-native complexes. In every case, docking the unbound ligands with flexible side chains led to better energies and a better distinction between near-native and non-native fits. An extension of this algorithm allowed for docking multiple residue substitutions (mutants) in addition to multiple conformations. The rankings of the docked mutant proteins correlated with experimental binding affinities. These results suggest that sampling multiple residue conformations and residue substitutions of the unbound ligand contributes to, but does not fully provide, a solution to the protein docking problem. Conformational sampling allows a classical atomistic scoring function to be used; such a function may contribute to better selectivity between near-native and non-native complexes. Allowing for receptor flexibility may further extend these results. [source] Water molecules in the crystal structure of tricyclic acyclovirACTA CRYSTALLOGRAPHICA SECTION C, Issue 6 2001Kinga Suwi The biologically important molecule tricyclic acyclovir, presented here as 3-[(2-hydroxyethoxy)methyl]-6-methyl-3H -imidazolo[1,2- a]purin-9(5H)-one dihydrate, C11H13N5O3·2H2O, shows conformational flexibility, which is observed in the solid state as two symmetrically independent molecules with different side-chain conformations. Additionally, one of these molecules exhibits side-chain disorder, such that there are three different conformations in the crystal. Water molecules found in the crystal form (H2O)8 clusters which are located between molecules of tricyclic acyclovir. The complex hydrogen-bond network formed between water and tricyclic acyclovir in the solid state may be related to the solvation of the molecules in solution. [source] Structure of Alzheimer's disease amyloid precursor protein copper-binding domain at atomic resolutionACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 10 2007Geoffrey Kwai-Wai Kong Amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's disease, as its cleavage generates the A, peptide that is toxic to cells. APP is able to bind Cu2+ and reduce it to Cu+ through its copper-binding domain (CuBD). The interaction between Cu2+ and APP leads to a decrease in A, production and to alleviation of the symptoms of the disease in mouse models. Structural studies of CuBD have been undertaken in order to better understand the mechanism behind the process. Here, the crystal structure of CuBD in the metal-free form determined to ultrahigh resolution (0.85,Å) is reported. The structure shows that the copper-binding residues of CuBD are rather rigid but that Met170, which is thought to be the electron source for Cu2+ reduction, adopts two different side-chain conformations. These observations shed light on the copper-binding and redox mechanisms of CuBD. The structure of CuBD at atomic resolution provides an accurate framework for structure-based design of molecules that will deplete A, production. [source] Monellin (MNEI) at 1.15,Å resolutionACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2007J. R. Hobbs The X-ray crystal structure of a single-chain monellin protein (MNEI) has been determined at 1.15,Å resolution. The model was refined to convergence employing anisotropic displacement parameters and riding H atoms to produce a final model with Rwork and Rfree values of 0.132 and 0.162, respectively. The crystal contains a single MNEI protein in the asymmetric unit and unusually lacks the dimer interface observed in all previous crystal structures of monellin and its single-chain derivatives. The high resolution allowed a more detailed view of MNEI than previously possible, with 38 of the 96 residues modelled with alternative side-chain conformations, including four core residues Thr12, Cys41, Leu62 and Ile75. Four stably bound negative ions were also located, providing new insight into potential electrostatic interactions of MNEI with the largely negatively charged surface of the sweet taste receptor T1R2,T1R3. [source] | ||||||||||