Semianalytical treatment of solvation for molecular mechanics and dynamics

Still, W. Clark; Tempczyk, Anna; Hawley, Ralph C.; Hendrickson, Thomas F.

doi:10.1021/ja00172a038

Cited by 3,536 publications

(3,593 citation statements)

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“…45,46 Subsequently, the entire complexes were minimized for 200 steps. After minimization, the complexes were solvated with tleap in rectangular TIP3P water boxes, 47 resulting in box sizes of approximately 85 Å × 83 Å × 82 Å.…”

Section: ■ Methodsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

Chen

Wehle

Kuzmanovic³

et al. 2014

ACS Chem. Neurosci.

102

103

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Photochromic cholinesterase inhibitors were obtained from cis-1,2-α-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl-(AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved "photoswitchable". The AChE-induced β-amyloid (Aβ) aggregation assay gave further experimental support to this finding: Aβ 1−40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ringopen and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ringclosed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays.

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Section: ■ Methodsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

Chen

Wehle

Kuzmanovic³

et al. 2014

ACS Chem. Neurosci.

102

103

View full text Add to dashboard Cite

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“…Bostrom et al 21 have proposed that biologically active conformations should be within 3 kcal/mol of the global energy conformation as calculated with an implicit solvation model (GB/SA). 39 This methodology was adapted: First, a conformational search using MacroModel version 9.6 40 was performed of PP using the Optimized Potentials for Liquid Simulations All Atom, version 2005, force field (OPLS_2005), 41,42 resulting in the identification of nine minimum energy conformations. Then, a representative pose for each of the four subclusters from the IFD of PP in hSERT were selected, and rmsd calculations were performed between the pose and each of the nine minimum energy structures.…”

Section: ■ Methodsmentioning

confidence: 99%

Binding of the Amphetamine-like 1-Phenyl-piperazine to Monoamine Transporters

Severinsen

Kraft

Koldsø

et al. 2012

ACS Chem. Neurosci.

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ABSTRACT:The human serotonin transporter (hSERT), the human dopamine transporter (hDAT), and the human norepinephrine transporter (hNET) facilitate the active uptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Drugs of abuse such as MDMA (streetname "ecstasy") and certain 1-phenyl-piperazine (PP) analogs such as 1-(3-chlorophenyl)-piperazine (mCPP) elicit their stimulatory effect by elevating the synaptic concentration of serotonin by blocking or reversing the normal transport activity of hSERT. Recent data suggest that certain analogs of PP may be able to counteract the addictive effect of cocaine. Little is still known about the precise mechanism by which MDMA and PP analogs function at hSERT, hDAT, and hNET and even less is known about the specific protein−ligand interactions. In this study, we provide a comprehensive biochemical examination of a repertoire of PP analogs in hSERT, hDAT, and hNET. Combined with induced fit docking models and molecular dynamics simulations of PP and 1-(3-hydroxyphenyl)-piperazine (3-OH-PP) bound to hSERT and hDAT, we present detailed molecular insight into the promiscuous binding of PP analogs in the monoamine transporters. We find that PP analogs inhibit uptake as well as induce release in all three monoamine transporters. We also find that the selectivity of the PP analogs can be adjusted by carefully selecting substituents on the PP skeleton.

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“…10,13,24,26,27 However, its performance on larger molecules has generally not been as good, with the trend being more pronounced for molecules having large interior regions. 24,26 Since the GB model shares the same underlying physical approximation-continuum electrostatics-with the PB approach, it is natural, in optimizing the GB performance, to use the PB model as a reference.…”

Section: Improving the Generalized Born Approximationmentioning

confidence: 99%

“…The molecule is surrounded by a solvent of a high dielectric value ⑀ w (80 for water at 300 K). The GB model approximates ⌬G el by an analytical formula, 10,24 …”

Section: Introductionmentioning

confidence: 99%

Exploring protein native states and large‐scale conformational changes with a modified generalized born model

2004

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Implicit solvation models provide, for many applications, a reasonably accurate and computationally effective way to describe the electrostatics of aqueous solvation. Here, a popular analytical Generalized Born (GB) solvation model is modified to improve its accuracy in calculating the solvent polarization part of free energy changes in large-scale conformational transitions, such as protein folding. In contrast to an earlier GB model (implemented in the AMBER-6 program), the improved version does not overstabilize the native structures relative to the finite-difference PoissonBoltzmann continuum treatment. In addition to improving the energy balance between folded and unfolded conformers, the algorithm (available in the AMBER-7 and NAB molecular modeling packages) is shown to perform well in more than 50 ns of native-state molecular dynamics (MD) simulations of thioredoxin, protein-A, and ubiquitin, as well as in a simulation of Barnase/Barstar complex formation. For thioredoxin, various combinations of input parameters have been explored, such as the underlying gas-phase force fields and the atomic radii. The best performance is achieved with a previously proposed modification to the torsional potential in the Amber ff99 force field, which yields stable native trajectories for all of the tested proteins, with backbone root-mean-square deviations from the native structures being ϳ1.5 Å after 6 ns of simulation time. The structure of Barnase/Barstar complex is regenerated, starting from an unbound state, to within 1.9 Å relative to the crystal structure of the complex.

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Semianalytical treatment of solvation for molecular mechanics and dynamics

Cited by 3,536 publications

References 0 publications

Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

Binding of the Amphetamine-like 1-Phenyl-piperazine to Monoamine Transporters

Exploring protein native states and large‐scale conformational changes with a modified generalized born model

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