Additional file 1 of HLA-Clus: HLA class I clustering based on 3D structure

Additional file1. Figure S1: Comparison between the number of HLA class I alleles studied previously

Additional file 2 of HLA-Clus: HLA class I clustering based on 3D structure

Additional file2. Table S1: Example output of the Processing_pipeline function. Table S2: Example output of HC_pipeline function. Table S3: Example of anchor_dictionary parameter for NN_pipeline function. Table S4: Example output of NN_pipeline output

Quantum Chemical Characterization of the Reactions of Guanine with the Phenylnitrenium Ion

Density functional calculations at the B3LYP/6-311+G(2d,p)//pBP/DN* level predict all cationic adducts combining guanine, at either its N2, O6, N7, or C8 positions, with phenylnitrenium ion, at either its N, 2, or 4 positions, to be lower in energy than the separated reactants. This relative stability of all adducts is preserved after addition of aqueous solvation free energies computed at the SM2 level, although some leveling of the adduct relative energies one to another is predicted. Cations having the lowest relative energies in solution correspond structurally to those adducts most commonly found when guanine reacts with larger, biologically relevant nitrenium ions in vitro and in vivo. One of these, the N−C8 adduct, is stabilized both by a rearomatized phenyl ring and by the operation of an anomeric effect not found in any of the others. On the basis of energetic analysis, direct conversion of an N−N7 cation to an N−C8 cation according to a previously proposed mechanism is unlikely; however, an alternative rearrangement converting a 2-N7 cation to an N−C8 cation via the intermediacy of a five-membered ring may be operative in nitrenium ions with aromatic frameworks better able than phenyl to stabilize endocyclic cationic charge

Mechanism of Cdc25B Phosphatase with the Small Molecule Substrate <i>p</i>-Nitrophenyl Phosphate from QM/MM-MFEP Calculations

Cdc25B is a dual-specificity phosphatase that catalyzes the dephosphorylation of the Cdk2/CycA protein complex. This enzyme is an important regulator of the human cell cycle and has been identified as a potential anticancer target. In general, protein tyrosine phosphatases are thought to bind the dianionic form of the phosphate and employ general acid catalysis via the Asp residue in the highly conserved WPD-loop. However, the Cdc25 phosphatases form a special subfamily based on their distinct differences from other protein tyrosine phosphatases. Although Cdc25B contains the (H/V)CX5R catalytic motif present in all other protein tyrosine phosphatases, it lacks an analogous catalytic acid residue. No crystallographic data currently exist for the complex of Cdc25B with Cdk2/CycA, so in addition to its natural protein substrate, experimental and theoretical studies are often carried out with small molecule substrates. In an effort to gain understanding of the dephosphorylation mechanism of Cdc25B with a commonly used small molecule substrate, we have performed simulations of the rate-limiting step of the reaction catalyzed by Cdc25B with the substrate p-nitrophenyl phosphate using the recently developed QM/MM Minimum Free Energy Path method (Hu et al. J. Chem. Phys. 2008, 034105). We have simulated the first step of the reaction with both the monoanionic and the dianionic forms of the substrate, and our calculations favor a mechanism involving the monoanionic form. Thus, Cdc25 may employ a unique dephosphorylation mechanism among protein tyrosine phosphatases, at least in the case of the small molecule substrate p-nitrophenyl phosphate

HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales

HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. The core is well-tested, well-documented, and easy to install across computational platforms. The goal of the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, an abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program

Quantum Chemical Calculation of p<i>K</i>_as of Environmentally Relevant Functional Groups: Carboxylic Acids, Amines, and Thiols in Aqueous Solution

Developing accurate quantum chemical approaches for calculating p<i>K</i>_as is of broad interest. Useful accuracy can be obtained by using density functional theory (DFT) in combination with a polarizable continuum solvent model. However, some classes of molecules present problems for this approach, yielding errors greater than 5 p<i>K</i> units. Various methods have been developed to improve the accuracy of the combined strategy. These methods perform well but either do not generalize or introduce additional degrees of freedom, increasing the computational cost. The Solvation Model based on Density (SMD) has emerged as one of the most commonly used continuum solvent models. Nevertheless, for some classes of organic compounds, e.g., thiols, the p<i>K</i>_as calculated with the original SMD model show errors of 6–10 p<i>K</i> units, and we traced these errors to inaccuracies in the solvation free energies of the anions. To improve the accuracy of p<i>K</i>_as calculated with DFT and the SMD model, we developed a scaled solvent-accessible surface approach for constructing the solute–solvent boundary. By using a “direct” approach, in which all quantities are computed in the presence of the continuum solvent, the use of thermodynamic cycles is avoided. Furthermore, no explicit water molecules are required. Three benchmark data sets of experimentally measured p<i>K</i>_a values, including 28 carboxylic acids, 10 aliphatic amines, and 45 thiols, were used to assess the optimized SMD model, which we call SMD with a scaled solvent-accessible surface (SMD_sSAS). Of the methods tested, the M06-2X density functional approximation, 6-31+G­(d,p) basis set, and SMD_sSAS solvent model provided the most accurate p<i>K</i>_as for each set, yielding mean unsigned errors of 0.9, 0.4, and 0.5 p<i>K</i> units, respectively, for carboxylic acids, aliphatic amines, and thiols. This approach is therefore useful for efficiently calculating the p<i>K</i>_as of environmentally relevant functional groups

Quantum Chemical Calculation of p<i>K</i>_as of Environmentally Relevant Functional Groups: Carboxylic Acids, Amines, and Thiols in Aqueous Solution

Developing accurate quantum chemical approaches for calculating pKas is of broad interest. Useful accuracy can be obtained by using density functional theory (DFT) in combination with a polarizable continuum solvent model. However, some classes of molecules present problems for this approach, yielding errors greater than 5 pK units. Various methods have been developed to improve the accuracy of the combined strategy. These methods perform well but either do not generalize or introduce additional degrees of freedom, increasing the computational cost. The Solvation Model based on Density (SMD) has emerged as one of the most commonly used continuum solvent models. Nevertheless, for some classes of organic compounds, e.g., thiols, the pKas calculated with the original SMD model show errors of 6–10 pK units, and we traced these errors to inaccuracies in the solvation free energies of the anions. To improve the accuracy of pKas calculated with DFT and the SMD model, we developed a scaled solvent-accessible surface approach for constructing the solute–solvent boundary. By using a “direct” approach, in which all quantities are computed in the presence of the continuum solvent, the use of thermodynamic cycles is avoided. Furthermore, no explicit water molecules are required. Three benchmark data sets of experimentally measured pKa values, including 28 carboxylic acids, 10 aliphatic amines, and 45 thiols, were used to assess the optimized SMD model, which we call SMD with a scaled solvent-accessible surface (SMDsSAS). Of the methods tested, the M06-2X density functional approximation, 6-31+G­(d,p) basis set, and SMDsSAS solvent model provided the most accurate pKas for each set, yielding mean unsigned errors of 0.9, 0.4, and 0.5 pK units, respectively, for carboxylic acids, aliphatic amines, and thiols. This approach is therefore useful for efficiently calculating the pKas of environmentally relevant functional groups

Mercury Methylation by HgcA: Theory Supports Carbanion Transfer to Hg(II)

Many proteins use corrinoid cofactors to facilitate methyl transfer reactions. Recently, a corrinoid protein, HgcA, has been shown to be required for the production of the neurotoxin methylmercury by anaerobic bacteria. A strictly conserved Cys residue in HgcA was predicted to be a lower-axial ligand to Co­(III), which has never been observed in a corrinoid protein. Here, we use density functional theory to study homolytic and heterolytic Co–C bond dissociation and methyl transfer to Hg­(II) substrates with model methylcobalamin complexes containing a lower-axial Cys or His ligand to cobalt, the latter of which is commonly found in other corrinoid proteins. We find that Cys thiolate coordination to Co facilitates both methyl radical and methyl carbanion transfer to Hg­(II) substrates, but carbanion transfer is more favorable overall in the condensed phase. Thus, our findings are consistent with HgcA representing a new class of corrinoid protein capable of transferring methyl groups to electrophilic substrates

Toward Quantitatively Accurate Calculation of the Redox-Associated Acid–Base and Ligand Binding Equilibria of Aquacobalamin

Redox processes in complex transition metal-containing species are often intimately associated with changes in ligand protonation states and metal coordination number. A major challenge is therefore to develop consistent computational approaches for computing pH-dependent redox and ligand dissociation properties of organometallic species. Reduction of the Co center in the vitamin B12 derivative aquacobalamin can be accompanied by ligand dissociation, protonation, or both, making these properties difficult to compute accurately. We examine this challenge here by using density functional theory and continuum solvation to compute Co–ligand binding equilibrium constants (<i>K</i>_on/off), p<i>K</i>_as, and reduction potentials for models of aquacobalamin in aqueous solution. We consider two models for cobalamin ligand coordination: the first follows the hexa, penta, tetra coordination scheme for Co^III, Co^II, and Co^I species, respectively, and the second model features saturation of each vacant axial coordination site on Co^II and Co^I species with a single, explicit water molecule to maintain six directly interacting ligands or water molecules in each oxidation state. Comparing these two coordination schemes in combination with five dispersion-corrected density functionals, we find that the accuracy of the computed properties is largely independent of the scheme used, but including only a continuum representation of the solvent yields marginally better results than saturating the first solvation shell around Co throughout. PBE performs best, displaying balanced accuracy and superior performance overall, with RMS errors of 80 mV for seven reduction potentials, 2.0 log units for five p<i>K</i>_as and 2.3 log units for two log <i>K</i>_on/off values for the aquacobalamin system. Furthermore, we find that the BP86 functional commonly used in corrinoid studies suffers from erratic behavior and inaccurate descriptions of Co–axial ligand binding, leading to substantial errors in predicted p<i>K</i>_as and <i>K</i>_on/off values. These findings demonstrate the effectiveness of the present approach for computing electrochemical and thermodynamic properties of a complex transition metal-containing cofactor

Quantum Chemical Approach for Calculating Stability Constants of Mercury Complexes

Stability constants are central to the multiscale modeling of the thermodynamic speciation, cycling, and transport of mercury (Hg) and other contaminants in aquatic environments. However, for Hg, experimental values for many relevant complexes are not available, and for others can span ranges in excess of 10 log units. The missing data and large uncertainties lead to significant knowledge gaps in predictions of thermodynamic speciation. As an alternative to experimental measurements, thermodynamic quantities can be calculated with quantum chemical methods. Among these, density functional theory (DFT) with a polarizable continuum solvent combines accuracy with practicability. Here, we present an accurate and quick approach in which we use DFT with continuum solvation to calculate stability constants of Hg complexes with inorganic and low molecular-weight organic ligands in aqueous solution. Specifically, we use the M06/[SDD]­6-31+G­(d,p) level of theory in combination with a modified version of the SMD solvent model in which the solute radii are reoptimized with a scaled solvent-accessible surface approach. For the set of 37 Hg complexes used for optimization, which contain environmentally relevant functional groups and have reliable experimental stability constants, we obtain a mean unsigned error of 1.4 log units. Testing the method on an independent set of 12 Hg complexes reproduces the experimental stability constants to a mean unsigned error of 1.6 log units. This approach is a substantial step toward generally applicable rapid stability constant derivation for a wide range of Hg complexes, including those present in dissolved organic matter