Computer simulations of ligand–protein binding with ensembles of protein conformations: A Monte Carlo study of HIV‐1 protease binding energy landscapes

We present the results of molecular docking simulations with HIV‐1 protease for the sb203386 and skf107457 inhibitors by Monte Carlo simulated annealing. A simplified piecewise linear energy function, the standard AMBER force field, and the AMBER force field with solvation and a soft‐core smoothing component are employed in simulations with a single‐protein conformation to determine the relationship between docking simulations with a simple energy function and more realistic force fields. The temperature‐dependent binding free energy profiles of the inhibitors interacting with a single protein conformation provide a detailed picture of relative thermodynamic stability and a distribution of ligand binding modes in agreement with experimental crystallographic data. Using the simplified piecewise linear energy function, we also performed Monte Carlo docking simulations with an ensemble of protein conformations employing preferential biased sampling of low‐energy protein conformations, and the results are analyzed in connection with the free energy profiles. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 72: 73–84, 1999     

Deciphering common failures in molecular docking of ligand-protein complexes

Common failures in predicting crystal structures of ligand-protein complexes are investigated for three ligand-protein systems by a combined thermodynamic and kinetic analysis of the binding energy landscapes. Misdocked predictions in ligand-protein docking are classified as `soft' and `hard' failures. While a soft failure arises when the search algorithm is unable to find the global energy minimum corresponding to the crystal structure, a hard failure results from a flaw of the energy function to qualify the crystal structure as the predicted lowest energy conformation in docking simulations. We find that neither the determination of a single structure with the lowest energy nor finding the most common binding mode is sufficient to predict crystal structures of the complexes, which belong to the category of hard failures. In a proposed hierarchical approach, structural similarity clustering of the conformations, generated from equilibrium simulations with the simplified energy function, is followed by energy refinement with the AMBER force field. This protocol, that involves a hierarchy of energy functions, resolves some common failures in ligand-protein docking and detects crystallographic binding modes that were not found during docking simulations.     

Electrophilicity versus Electrofugality of Tritylium Ions in Aqueous Acetonitrile

First‐order rate constants k_w for the reactions of a series of donor‐substituted triphenylmethylium (tritylium) ions with water in aqueous acetonitrile have been determined photometrically at 20 °C using stopped‐flow and laser‐flash techniques. The rate constants follow the linear free energy relationship log k(20 °C)=s(N+E). The reactivities k_w of the methyl‐ and methoxy‐substituted tritylium ions towards water correlate linearly with the corresponding pK values with a Leffler–Hammond coefficient α=δΔG^≠/δΔG⁰ of 0.62. The amino‐substituted compounds react more slowly than expected from the correlation of the less stabilized systems. Quantum chemical calculations of tritylium ions and the corresponding triarylmethanols and 1,1,1‐triarylethanes have been performed at the MP2(FC)/6‐31+G(2d,p)//B3LYP/6‐31G(d,p) level. The calculated gas‐phase hydroxide and methyl anion affinities of the tritylium ions correlate linearly with a slope of unity, indicating that the relative anion affinities do not depend on the nature of the anion. The pK values of the methyl‐ and methoxy‐substituted tritylium ions correlate linearly with the calculated gas‐phase hydroxide affinities, and the slope of this correlation shows that the differences in carbocation stabilities in the gas phase are attenuated to 66 % in solution. Mono‐ and bis(dimethylamino)‐substituted derivatives deviate from this correlation; their pK values are higher than expected from their calculated gas‐phase hydroxide affinities, which is explained by the extraordinary solvation of unsymmetrically amino‐substituted tritylium ions. Complete free‐energy profiles for the solvolyses of substituted trityl benzoates in 90:10 (v/v) acetonitrile/water have been constructed.     

Prediction of protein–protein complexes using replica exchange with repulsive scaling

The realistic prediction of protein–protein complex structures is import to ultimately model the interaction of all proteins in a cell and for the design of new protein–protein interactions. In principle, molecular dynamics (MD) simulations allow one to follow the association process under realistic conditions including full partner flexibility and surrounding solvent. However, due to the many local binding energy minima at the surface of protein partners, MD simulations are frequently trapped for long times in transient association states. We have designed a replica-exchange based scheme employing different levels of a repulsive biasing between partners in each replica simulation. The bias acts only on intermolecular interactions based on an increase in effective pairwise van der Waals radii (repulsive scaling (RS)-REMD) without affecting interactions within each protein or with the solvent. For a set of five protein test cases (out of six) the RS-REMD technique allowed the sampling of near-native complex structures even when starting from the opposide site with respect to the native binding site for one partner. Using the same start structures and same computational demand regular MD simulations sampled near native complex structures only for one case. The method showed also improved results for the refinement of docked structures in the vicinity of the native binding geometry compared to regular MD refinement.     

手性锌卟啉的圆二色光谱研究

用圆二色光谱（CD）研究了三种新型手性卟啉锌[α,β,α,β－四－[邻（叔丁氧羰L－丙氨酸）氨基苯基]卟啉锌α,β,α,β,－ZnT(o-BocAla)APP1、α,β,α,β-四－[邻（叔丁氧羰L－脯氨酸）氨基苯基]卟啉锌α,β,α,β－ZnT(o-BocPro)APP2和α,β,α,β－甲－[邻（苯甲酰L－谷酰胺）氨基苯基]卟啉锌α,β,α,β－ZnT(o-BenzoylGln)APP3]在CH2Cl2 中的光谱行为,并研究了1作为主体识别手性客体分子氨基酸甲酯前后的光谱,提出了光谱形成机理。     

Bis coumarinyl bis triazolothiadiazinyl ethane derivatives: Synthesis,antiviral activity evaluation,and molecular docking studies

A series of novel 3,3′-(3,3′-(dihydroxy/hydroxyethane-1,2-diyl)bis(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6,3-diyl))bis(2H-chromen-2-ones) were prepared by the condensation of thiocarbohydrazide with tartaric acid or malic acid followed by various 3-(2-bromoacetyl)-2H-chromen-2-ones in two steps with good yields. All the synthesized compounds were characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR, and mass) data. These synthesized bis(triazolothiadiazinyl coumarin) compounds were evaluated for broad spectrum of antiviral activity. Among all the tested compounds, compound 5f exhibited antiviral activity against H1N1 virus. The molecular docking studies of these compounds against H1N1 neuraminidase enzyme were performed. The binding affinity and binding values were compared with standard drugs.     

Trapping of Organophosphorus Chemical Nerve Agents in Water with Amino Acid Functionalized Baskets

We prepared eleven amino‐acid functionalized baskets and used ¹H NMR spectroscopy to quantify their affinity for entrapping dimethyl methylphosphonate (DMMP, 118 ų) in aqueous phosphate buffer at pH=7.0±0.1; note that DMMP guest is akin in size to chemical nerve agent sarin (132 ų). The binding interaction (K_a) was found to vary with the size of substituent groups at the basket′s rim. In particular, the degree of branching at the first carbon of each substituent had the greatest effect on the host‐guest interaction, as described with the Verloop′s B1 steric parameter. The branching at the remote carbons, however, did not perturb the encapsulation, which is important for guiding the design of more effective hosts and catalysts in future.     

Fine‐Tuning the Nucleophilic Reactivities of Boron Ate Complexes Derived from Aryl and Heteroaryl Boronic Esters

Boron ate complexes derived from thienyl and furyl boronic esters and aryllithium compounds have been isolated and characterized by X‐ray crystallography. Products and mechanisms of their reactions with carbenium and iminium ions have been analyzed. Kinetics of these reactions were monitored by UV/Vis spectroscopy, and the influence of the aryl substituents, the diol ligands (pinacol, ethylene glycol, neopentyl glycol, catechol), and the counterions on the nucleophilic reactivity of the boron ate complexes were examined. A Hammett correlation confirmed the polar nature of their reactions with benzhydrylium ions, and the correlation lg k(20 °C)=s_N(E+N) was employed to determine the nucleophilicities of the boron ate complexes and to compare them with those of other borates and boronates. The neopentyl and ethylene glycol derivatives were found to be 10⁴ times more reactive than the pinacol and catechol derivatives.     

Nucleophilic reactivities of the anions of nucleobases and their subunits

The kinetics of the reactions of different heterocyclic anions derived from imidazoles, purines, pyrimidines, and related compounds with benzhydrylium ions and structurally related quinone methides have been studied in DMSO and water. The second-order rate constants (log k(2)) correlated linearly with the electrophilicity parameters E of the electrophiles according to the correlation log k(2) = s(N)(N+E) (H. Mayr, M. Patz, Angew. Chem. 1994, 106, 990-1010; Angew. Chem. Int. Ed. Engl. 1994, 33, 938-957) allowing us to determine the nucleophilicity parameters N and s(N) for these anions. In DMSO, the reactivities of these heterocyclic anions vary by more than six orders of magnitude and are comparable to carbanions, amide and imide anions, or amines. The azole anions are generally four to five orders of magnitude more reactive than their conjugate acids.