4 research outputs found
Release of cclib version 1.5
<p>This is an archive of the source code for cclib version 1.5, orginally released on github (https://github.com/cclib/cclib/releases/tag/v1.5).</p
Nonempirical Energetic Analysis of Reactivity and Covalent Inhibition of Fatty Acid Amide Hydrolase
Fatty acid amide hydrolase (FAAH)
is a member of the amidase signature
family and is responsible for the hydrolytic deactivation of fatty
acid amide neuromodulators, such as anandamide. FAAH carries an unusual
catalytic triad consisting of Lys-Ser-Ser, which uniquely enables
the enzyme to cleave amides and esters at similar rates. The acylation
of 9<i>Z</i>-octadecenamide (oleamide, a FAAH reference
substrate) has been widely investigated by computational methods,
and those have shown that conformational fluctuations of the active
site affect the reaction barrier. Empirical descriptors have been
devised to provide a possible mechanistic explanation for such conformational
effects, but a first-principles understanding is still missing. A
comparison of FAAH acylation with a reference reaction in water suggests
that transition-state stabilization is crucial for catalysis because
the activation energy barrier falls by 6 kcal/mol in the presence
of the active site. With this in mind, we have analyzed the enzymatic
reaction using the differential transition-state stabilization (DTSS)
approach to determine key active-site residues for lowering the barrier.
We examined several QM/MM structures at the MP2 level of theory and
analyzed catalytic effects with a variation–perturbation partitioning
of the interaction energy into electrostatic multipole and penetration,
exchange, delocalization, and correlation terms. Three residues –
Thr236, Ser218, and one water molecule – appear to be essential
for the stabilization of the transition state, a conclusion that is
also reflected by catalytic fields and agrees with site-directed mutagenesis
data. An analogous analysis for URB524, URB618, and URB694 (three
potent representatives of covalent, carbamate-based FAAH inhibitors)
confirms the importance of the residues involved in oleamide acylation,
providing insight for future inhibitor design
Electric Field Induced Selective Disordering in Lamellar Block Copolymers
External electric fields align nanostructured block copolymers by either rotation of grains or nucleation and growth depending on how strongly the chemically distinct block copolymer components are segregated. In close vicinity to the order–disorder transition, theory and simulations suggest a third mechanism: selective disordering. We present a time-resolved small-angle X-ray scattering study that demonstrates how an electric field can indeed selectively disintegrate ill-aligned lamellae in a lyotropic block copolymer solution, while lamellae with interfaces oriented parallel to the applied field prevail. The present study adds an additional mechanism to the experimentally corroborated suite of mechanistic pathways, by which nanostructured block copolymers can align with an electric field. Our results further unveil the benefit of electric field assisted annealing for mitigating orientational disorder and topological defects in block copolymer mesophases, both in close vicinity to the order–disorder transition and well below it