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1.  Weakly Antiferromagentic Coupling Via Superexchange Interaction Between Mn(II)-Mn(II) Atoms: A QM/MM Study of the Active Site of Human Cytosolic X-Propyl Aminopeptidase P 
We investigate the dinuclear manganese, Mn(II)-Mn(II), active site of human cytosolic X-propyl aminopeptidase (XPNPEP1) employing the QM/MM method. The optimized structure supports two manganese atoms at the active site and excludes the possibility of a single Mn(II) atom or other combination of divalent metal ions: Ca(II), Fe(II), Mg(II). A broken symmetry solution verifies an antiferromagnetically coupled state between the Mn(II)-Mn(II) pair, which is the ground state. From the energy difference between the high spin state (HS) and the broken symmetry state (BS), we estimate the exchange coupling constant, J, to be 5.15 cm-1. Also, we observe multiple bridges (p orbitals) from solvent and two carboxylate linking to the Mn(II)-Mn(II), which leads to the weakly antiferromagnetic interaction of d5-d5 electrons through superexchange coupling.
doi:10.1021/jz300768g
PMCID: PMC3491985  PMID: 23145216
Dinuclear Manganese Atoms; Broken Symmetry; Enzyme; EPR; μ-carboxylato bridge; μ-H2O bridge
2.  Cheminformatics Meets Molecular Mechanics: A Combined Application of Knowledge-based Pose Scoring and Physical Force Field-based Hit Scoring Functions Improves the Accuracy of Structure-Based Virtual Screening 
Poor performance of scoring functions is a well-known bottleneck in structure-based virtual screening, which is most frequently manifested in the scoring functions’ inability to discriminate between true ligands versus known non-binders (therefore designated as binding decoys). This deficiency leads to a large number of false positive hits resulting from virtual screening. We have hypothesized that filtering out or penalizing docking poses recognized as non-native (i.e., pose decoys) should improve the performance of virtual screening in terms of improved identification of true binders. Using several concepts from the field of cheminformatics, we have developed a novel approach to identifying pose decoys from an ensemble of poses generated by computational docking procedures. We demonstrate that the use of target-specific pose (-scoring) filter in combination with a physical force field-based scoring function (MedusaScore) leads to significant improvement of hit rates in virtual screening studies for 12 of the 13 benchmark sets from the clustered version of the Database of Useful Decoys (DUD). This new hybrid scoring function outperforms several conventional structure-based scoring functions, including XSCORE∷HMSCORE, ChemScore, PLP, and Chemgauss3, in six out of 13 data sets at early stage of VS (up 1% decoys of the screening database). We compare our hybrid method with several novel VS methods that were recently reported to have good performances on the same DUD data sets. We find that the retrieved ligands using our method are chemically more diverse in comparison with two ligand-based methods (FieldScreen and FLAP∷LBX). We also compare our method with FLAP∷RBLB, a high-performance VS method that also utilizes both the receptor and the cognate ligand structures. Interestingly, we find that the top ligands retrieved using our method are highly complementary to those retrieved using FLAP∷RBLB, hinting effective directions for best VS applications. We suggest that this integrative virtual screening approach combining cheminformatics and molecular mechanics methodologies may be applied to a broad variety of protein targets to improve the outcome of structure-based drug discovery studies.
doi:10.1021/ci2002507
PMCID: PMC3264743  PMID: 22017385
3.  Construction of Cyclopentanol Derivatives via Three-Component Coupling of Silyl Glyoxylates, Acetylides, and Nitroalkenes 
Organic Letters  2012;14(2):652-655.
The three-component coupling of Mg-acetylides, silyl glyoxylates, and nitroalkenes results in a highly diastereoselective Kuwajima-Reich/vinylogous Michael cascade that provides tetrasubstituted silyloxyallene products. The regio- and diastereoselectivity were studied using DFT calculations. These silyloxyallenes were converted to cyclopentenols and cyclopentitols via a unique Lewis-acid assisted Henry cyclization. The alkene functionality present in the cyclopentanol products can be elaborated using diastereoselective ketohydroxylation reactions.
doi:10.1021/ol2033527
PMCID: PMC3265386  PMID: 22235777
4.  Combined application of cheminformatics- and physical force field-based scoring functions improves binding affinity prediction for CSAR datasets 
The curated CSAR-NRC benchmark sets provide valuable opportunity for testing or comparing the performance of both existing and novel scoring functions. We apply two different scoring functions, both independently and in combination, to predict binding affinity of ligands in the CSAR-NRC datasets. One, reported here for the first time, employs multiple chemical-geometrical descriptors of the protein-ligand interface to develop Quantitative Structure – Binding Affinity Relationships (QSBAR) models; these models are then used to predict binding affinity of ligands in the external dataset. Second is a physical force field-based scoring function, MedusaScore. We show that both individual scoring functions achieve statistically significant prediction accuracies with the squared correlation coefficient (R2) between actual and predicted binding affinity of 0.44/0.53 (Set1/Set2) with QSBAR models and 0.34/0.47 (Set1/Set2) with MedusaScore. Importantly, we find that the combination of QSBAR models and MedusaScore into consensus scoring function affords higher prediction accuracy than any of the contributing methods achieving R2 of 0.45/0.58 (Set1/Set2). Furthermore, we identify several chemical features and non-covalent interactions that may be responsible for the inaccurate prediction of binding affinity for several ligands by the scoring functions employed in this study.
doi:10.1021/ci200146e
PMCID: PMC3183266  PMID: 21780807
5.  A hetero-dimer model for concerted action of vitamin K carboxylase and vitamin K reductase in vitamin K cycle 
Journal of theoretical biology  2011;279(1):143-149.
Vitamin K carboxylase (VKC) is believed to convert vitamin K, in the vitamin K cycle, to an alkoxide-epoxide form which then reacts with CO2 and glutamate to generate γ-carboxyglutamic acid (Gla). Subsequently, vitamin K epoxide reductase (VKOR) is thought to convert the alkoxide-epoxide to a hydroquinone form. By recycling vitamin K, the two integral-membrane proteins, VKC and VKOR, maintain vitamin K levels and sustain the blood coagulation cascade. Unfortunately, NMR or X-ray crystal structures of the two proteins have not been characterized. Thus, our understanding of the vitamin K cycle is only partial at the molecular level. In this study, based on prior biochemical experiments on VKC and VKOR, we propose a hetero-dimeric form of VKC and VKOR that may explain the efficient oxidation and reduction of vitamin K during the vitamin K cycle.
doi:10.1016/j.jtbi.2011.03.030
PMCID: PMC3108363  PMID: 21453708
vitamin K cycle; vitamin K carboxylase; vitamin K epoxide reductase; hetero-dimer
6.  Regioselectivity of Catechol O-Methyltransferase Confers Enhancement of Catalytic Activity 
Chemical physics letters  2011;506(4-6):135-138.
Catechol O-methyltransferase (COMT) metabolizes catechol moieties by methylating a single hydroxyl group at the meta- or para- hydroxyl position. Hydrophobic amino acids near the active site of COMT influence the regioselectivity of this reaction. Our sequence analysis highlights their importance by showing that these residues are highly conserved throughout evolution. Reaction barriers calculated in the gas phase reveal a lower barrier during methylation at the meta- position, suggesting that the observed meta-regioselectivity of COMT can be attributed to the substrate itself, and that COMT has evolved residues to orient the substrate in a manner that increases the rate of catalysis.
doi:10.1016/j.cplett.2011.03.048
PMCID: PMC3125089  PMID: 21731105
7.  Quantum Chemical Study of the Mechanism of Action of Vitamin K Carboxylase in Solvent 
We investigate the post-translational generation of Gla (γ-carboxy glutamic acid) from Glu (glutamic acid) by vitamin K carboxylase (VKC) in solvent. VKC is thought to convert vitamin K, in the vitamin K cycle, to an alkoxide-epoxide form, which then reacts with CO2 to generate an essential ingredient in blood coagulation, γ-carboxyglutamic acid (Gla). The generation of Gla from Glu is found to be exergenic (−15 kcal/mol) in aqueous solution with the SM6 method. We also produced the free energy profile for this model biochemical process with other solvent methods (polarizable continuum model, dielectric polarizable continuum model) and different dielectric constants. The biological implications are discussed.
doi:10.1002/qua.22740
PMCID: PMC3164839  PMID: 21892230
vitamin K cycle; Dowd mechanism; free energy profile; solvent; heterodimer
8.  Steric, Quantum, and Electrostatic Effects on SN2 Reaction Barriers in Gas Phase 
The journal of physical chemistry. A  2010;114(18):5913-5918.
Biomolecular nucleophilic substitution reactions, SN2, are fundamental and commonplace in chemistry. It is the well documented experimental finding in the literature that vicinal substitution with bulkier groups near the reaction center significantly slows the reaction due to steric hindrance, but theoretical understanding in the quantitative manner about factors dictating the SN2 reaction barrier height is still controversial. In this work, employing the new quantification approach that we recently proposed for the steric effect from the density functional theory framework, we investigate the relative contribution of three independent effects, steric, electrostatic, and quantum, to the SN2 barrier heights in gas phase for substituted methyl halide systems, R1R2R3CX, reacting with fluorine anion where R1, R2, and R3 denote substituting groups and X=F or Cl. We found that in accordance with the experimental finding, for these systems the steric effect dominates the transition state barrier, contributing positively to barrier heights, but this contribution is largely compensated by the negative, stabilizing contribution from the quantum effect due to the exchange-correlation interactions. Moreover, we find that it is the component from the electrostatic effect that is linearly correlated with the SN2 barrier height for the systems investigated in the present study. In addition, we compared our approach with the conventional method of energy decomposition in density functional theory, as well as examined the steric effect from the wavefunction theory for these systems via the natural bond orbital analysis.
doi:10.1021/jp101329f
PMCID: PMC2865848  PMID: 20377265
9.  Multiscale approaches for studying energy transduction in dynein 
Cytoplasmic dynein is an important motor that drives all minus-end directed movement along microtubules. Dynein is a complex motor whose processive motion is driven by ATP-hydrolysis. Dynein's run length has been measured to be several millimetres with typical velocities in the order of a few nanometres per second. Therefore, the average time between steps is a fraction of a second. When this time scale is compared with typical time scales for protein side chain and backbone movements (~10−9 s and ~10−5 s, respectively), it becomes clear that a multi-timescale modelling approach is required to understand energy transduction in this protein. Here, we review recent efforts to use computational and mathematical modelling to understand various aspects of dynein's chemomechanical cycle. First, we describe a structural model of dynein's motor unit showing a heptameric organization of the motor subunits. Second, we describe our molecular dynamics simulations of the motor unit that are used to investigate the dynamics of the various motor domains. Third, we present a kinetic model of the coordination between the two dynein heads. Lastly, we investigate the various potential geometries of the dimer during its hydrolytic and stepping cycle.
doi:10.1039/b902028d
PMCID: PMC2823375  PMID: 19506759
10.  Estimation of Molecular Acidity via Electrostatic Potential at the Nucleus and Valence Natural Atomic Orbitals 
The journal of physical chemistry. A  2009;113(15):3648-3655.
An effective approach of estimating molecular pKa values from simple density functional calculations is proposed in this work. Both the molecular electrostatic potential (MEP) at the nucleus of the acidic atom and the sum of valence natural atomic orbitals are employed for three categories of compounds, amines and anilines, carbonyl acids and alcohols, and sulfonic acids and thiols. A strong correlation between experimental pKa values and each of these two quantities for each of the three categories has been discovered. Moreover, if the MEP is subtracted by the isolated atomic MEP for each category of compounds, we observe a single unique linear relationship between the resultant MEP difference and experimental pKa data of amines, anilines, carbonyl acids, alcohols, sulfonic acids, thiols, and their substituents. These results can generally be utilized to simultaneously estimate pKa values at multiple sites with a single calculation for either relatively small molecules in drug design or amino acids in proteins and macromolecules.
doi:10.1021/jp811250r
PMCID: PMC2670071  PMID: 19317439

Results 1-10 (10)