Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II and degrades bradykinin and other vasoactive peptides. ACE inhibitors are used to treat diseases such as hypertension and heart failure. It is thus highly desirable to understand the catalytic mechanism of ACE, as this should facilitate the design of more powerful and selective ACE inhibitors. ACE exhibits two different active domains, the C-domain and the N-domain. In this work, we systematically investigated the inhibitor- and substrate-binding patterns in the N-domain of human ACE using a combined quantum mechanical and molecular mechanical approach. The hydrolysis of hippuryl–histidyl–leucine (HHL) as catalyzed by the N-domain of human somatic ACE was explored, and the effects of chloride ion on the overall reaction were also investigated. Two models, one with and one without a chloride ion at the first binding position, were then designed to examine the chloride dependence of inhibitor–substrate binding and the catalytic mechanism. Our calculations indicate that the hydrolysis reaction follows a stepwise general base/general acid catalysis path. The estimated mean free energy barrier height in the two models is about 15.6 kcal/mol, which agrees very well with the experimentally estimated value of 15.8 kcal/mol. Our simulations thus suggest that the N-domain is in a mixed form during ACE-catalyzed hydrolysis, with the single-chloride-ion and the double-chloride-ion forms existing simultaneously.
The effect of alkali metal oxides MnO (M?=?Li, Na, K; n?=?2, 3, 4) on the geometric, electronic, and linear and nonlinear optical properties of the Mg12O12 nanocage was investigated by density-functional-based methods. According to the computational results, these alkali metal oxides are adsorbed on the Mg12O12 nanocage because this adsorption reduces its energy gap. The static first hyperpolarizability (β0) of the nanocage is dramatically increased in the presence of the alkali metal oxides, with the greatest increase seen in the presence of the superalkalis (i.e., M3O; M?=?Li, Na, and K). The highest first hyperpolarizability (β0?≈?600,000 a.u.) was calculated for K3O@Mg12O12, which was considerably more than that for Mg12O12. The thermodynamic properties and relative stabilities of these inorganic compounds are discussed.
Electron transfer between cytochrome c (Cytc) and electrodes can be influenced greatly by the orientation of protein on the surface of the electrodes. In the present study, different initial orientations of Cytc on the surface of five types of single-walled carbon nanotubes (SWNTs), with different diameters and chirality, were constructed. Properties of the orientations of proteins on the surface of these tubes were first investigated through molecular dynamics simulations. It was shown that variations in SWNT diameter do not significantly affect the orientation; however, the chirality of the SWNTs is crucial to the orientation of the heme embedded in Cytc, and the orientation of the protein can consequently be influenced by the heme orientation. A new electron pathway between Cytc and SWNT, which hopefully benefits electron transfer efficiency, has also been proposed. This study promises to provide theoretical guidance for the rational design of bio-sensors or bio-fuel cells by using Cytc-decorated carbon nanotube electrodes. 相似文献
Elucidating the relationship between sequence and conformation is essential for the understanding of functions of proteins. While sharing 88 % sequence identity and differing by only seven residues, GA88 and GB88 have completely different structures and serve as ideal systems for investigating the relationship between sequence and function. Benefiting from the continuous advancement of the computational ability of modern computers, molecular dynamics (MD) simulation is now playing an increasingly important role in the study of proteins. However, the reliability of MD simulations is limited by the accuracy of the force fields and solvent model approximations. In this work, several AMBER force fields (AMBER03, AMBER99SB, AMBER12SB, AMBER14SB, AMBER96) and solvent models (TIP3P, IGB5, IGB7, IGB8) have been employed in the simulations of GA88 and GB88. The statistical results from 19 simulations show that GA88 and GB88 both adopt more compact structures than the native structures. GB88 is more stable than GA88 regardless of the force fields and solvent models utilized. Most of the simulations overestimated the salt bridge interaction. The combination of AMBER14SB force field and IGB8 solvent model shows the best overall performance in the simulations of both GA88 and GB88. AMBER03 and AMBER12SB also yield reasonable results but only in the TIP3P explicit solvent model. 相似文献
There are eight possible pathways for the iron-tricarbonyl-assisted thermal electrocyclic ring opening of fluorocyclobutene due to variations in the orientation of the binding of Fe(CO)3 relative to the fluorine substituent (R1 or R2), stereoselectivity (conrotatory or disrotatory, i.e., C or D), and the torquoselectivity of fluorine (inward-facing or outward-facing, i.e., in or out). A density functional study revealed that the energetically favored pathway is R1Din. Not only is the D mode favored energetically, but the in configuration was observed to be the lowest-lying mode of R1, despite the general tendency of fluorine substituents to prefer an out configuration. Data on the activation hardness and aromaticity indices such as BAC and HOMA lead to the same conclusion. However, the R2 mode surprisingly shows no particular preference for either the Cout or the Dout pathway (i.e., the R2 mode shows less stereoselectivity than R1). This behavior occurs due to the influences of both the fluorine substituent and metal coordination. Also, the geminal bond orbitals σ(C–F) and σ*(C–F) appear to participate in ring opening, given the excellent correlation of ?BE with the activation barrier of the transition state. 相似文献
The absorption and emission spectra of dichlorvos and the dichlorvos-MAA complex in methanol, water, and chloroform in the molecularly imprinted recognition were investigated systematically. The M06-2X results revealed that: 1) the hydroxyl groups in polar solvents such as methanol and water may markedly influence the weak interactions, and then alter the adsorption and emission spectra; 2) the electronic excitation in absorption spectra of dichlorvos is dominated by the configuration HOMO?→?LUMO, but in the most stable dichlorvos-MAA it becomes the ππ* excitation of HOMO?→?LUMO?+?1; 3) Mulliken charges reveal that dichlorvos almost dissociates to Cl- and a cation in its S1 excitation state; 4) the phosphorescence spectra of dichlorvos-MAA are relatively weak.
Graphical Abstract The absorption and emission spectra of dichlorvos and the dichlorvos-MAA complex in the molecularly imprinted recognition of dichlorvos were investigated systematically in methanol, water, and chloroform as solvents.
Single- and double-chain models of three stereoregular polymers, iso- and syndiotactic poly(methyl methacrylate) and isotactic poly(vinyl chloride), were extensively simulated using systematic coarse-grained (CG) potentials. It was found that, in vacuum, all of these long chains collapse in a two-stage process from their fully extended configurations into coils, and the two chains in each double-chain model ultimately become intertwined. Strong intermolecular interactions were found to occur between two chains of the same polymer (“like pairs”), which helps to explain the high densities of single-component melts. However, the intermolecular interactions between two chains of different polymers (“unlike pairs”) were stronger than those in like pairs. The enthalpy of mixing for unlike pairs—obtained from their intermolecular interaction energies—was negative, indicating that the two binary blends considered here are homogeneous systems. Moreover, a more negative enthalpy of mixing is suggested to correlate with better miscibility. These results agree well with corresponding experimental and simulated results, once again validating the accuracy of CG potentials when they are used to explore structural and energetic properties. The local structure captured by the isolated long chains dictates the ability to elucidate melt-phase behavior. A scheme involving the preparation of bulk models with initially collapsed chains was proposed; such CG models could be widely used to rapidly screen pairs of polymers for specific applications.
In the development of osteoarthritis, aggrecan degrades prior to cartilage destruction. Aggrecanase-1 (ADAMTS-4) is considered to be the major enzyme responsible for cleaving the Glu373–Ala374 bond in the interglobular domain of aggrecan in humans. Therefore, inhibitors of ADAMTS-4 have therapeutic potential in the treatment of osteoarthritis. In the present work, we developed a chemical feature based pharmacophore model of ADAMTS-4 inhibitors using the HipHop module within the Catalyst program package in order to elucidate the structure–activity relationship and to carry out in-silico screening. The Maybridge database was screened using Hypo1 as a 3D query, and the best-fit hits that followed Lipinski’s rule of five were subsequently screened to select the compounds. The hit compounds were then docked into the active site of ADAMTS-4, and interactions were visualized to determine the potential lead molecules. After subjecting all of the hits to various screening and filtering processes, 13 compounds were finally evaluated for their in vitro inhibitory activities. This study resulted in the identification of two lead compounds with potent inhibitory effects on ADAMTS-4 activity, with IC50 values of 0.042 μM and 0.028 μM, respectively. These results provide insight into the pharmacophoric requirements for the development of more potent ADAMTS-4 inhibitors.
Graphical Abstract The aggrecan-degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. In this work, we used HipHop-based pharmacophore modeling and virtual screening of the Maybridge database to identify novel ADAMTS-4 inhibitors. These novel lead compounds act as potent and specific inhibitors for the ADAMTS-4 enzyme and could have therapeutic potential in the treatment of OA
