3,402 research outputs found
Mapping Enzymatic Catalysis using the Effective Fragment Molecular Orbital Method: Towards all ab initio Biochemistry
We extend the Effective Fragment Molecular Orbital (EFMO) method to the
frozen domain approach where only the geometry of an active part is optimized,
while the many-body polarization effects are considered for the whole system.
The new approach efficiently mapped out the entire reaction path of chorismate
mutase in less than four days using 80 cores on 20 nodes, where the whole
system containing 2398 atoms is treated in the ab initio fashion without using
any force fields. The reaction path is constructed automatically with the only
assumption of defining the reaction coordinate a priori. We determine the
reaction barrier of chorismate mutase to be kcal mol for
MP2/cc-pVDZ and for MP2/cc-pVTZ in an ONIOM approach using
EFMO-RHF/6-31G(d) for the high and low layers, respectively.Comment: SI not attache
Dimensions, Maximal Growth Sites and Optimization in the Dielectric Breakdown Model
We study the growth of fractal clusters in the Dielectric Breakdown Model
(DBM) by means of iterated conformal mappings. In particular we investigate the
fractal dimension and the maximal growth site (measured by the Hoelder exponent
) as a function of the growth exponent of the DBM model.
We do not find evidence for a phase transition from fractal to non-fractal
growth for a finite -value. Simultaneously, we observe that the limit of
non-fractal growth () is consistent with .
Finally, using an optimization principle, we give a recipe on how to estimate
the effective value of from temporal growth data of fractal aggregates.Comment: 5 pages, 7 figures; v2: extra figures and new data adde
Empirical corrections and pair interaction energies in the fragment molecular orbital method
The energy and analytic gradient are developed for FMO combined with the
Hartree-Fock method augmented with three empirical corrections (HF-3c). The
auxiliary basis set approach to FMO is extended to perform pair interaction
energy decomposition analysis. The FMO accuracy is evaluated for several
typical systems including 3 proteins. Pair interaction energies computed with
different approaches in FMO are compared for a water cluster and protein-ligand
complexes.Comment: Revised version accepted in Chemical Physics Letter
A graph-based genetic algorithm and generative model/Monte Carlo tree search for the exploration of chemical space
This paper presents a comparison of a graph-based genetic algorithm (GB-GA) and machine learning (ML) results for the optimisation of logP values with a constraint for synthetic accessibility and shows that GA is as good or better than the ML approaches for this particular property. The molecules found by GB-GA bear little resemblance to the molecules used to construct the initial mating pool, indicating that the GB-GA approach can traverse a relatively large distance in chemical space using relatively few (50) generations. The paper also introduces a new non-ML graph-based generative model (GB-GM) that can be parameterized using very small data sets and combined with a Monte Carlo tree search (MCTS) algorithm. The results are comparable to previously published results (Sci. Technol. Adv. Mater. 2017, 18, 972-976) using a recurrent neural network (RNN) generative model, while the GB-GM-based method is orders of magnitude faster. The MCTS results seem more dependent on the composition of the training set than the GA approach for this particular property. Our results suggest that the performance of new ML-based generative models should be compared to more traditional, and often simpler, approaches such a GA
Hybrid RHF/MP2 geometry optimizations with the Effective Fragment Molecular Orbital Method
The frozen domain effective fragment molecular orbital method is extended to
allow for the treatment of a single fragment at the MP2 level of theory. The
approach is applied to the conversion of chorismate to prephenate by chorismate
mutase, where the substrate is treated at the MP2 level of theory while the
rest of the system is treated at the RHF level. MP2 geometry optimization is
found to lower the barrier by up to 3.5 kcal/mol compared to RHF optimzations
and ONIOM energy refinement and leads to a smoother convergence with respect to
the basis set for the reaction profile. For double zeta basis sets the increase
in CPU time relative to RHF is roughly a factor of two.Comment: 11 pages, 3 figure
In silico prediction of mutant HIV-1 proteases cleaving a target sequence
HIV-1 protease represents an appealing system for directed enzyme re-design,
since it has various different endogenous targets, a relatively simple
structure and it is well studied. Recently Chaudhury and Gray (Structure (2009)
17: 1636 -- 1648) published a computational algorithm to discern the
specificity determining residues of HIV-1 protease. In this paper we present
two computational tools aimed at re-designing HIV-1 protease, derived from the
algorithm of Chaudhuri and Gray. First, we present an energy-only based
methodology to discriminate cleavable and non cleavable peptides for HIV-1
proteases, both wild type and mutant. Secondly, we show an algorithm we
developed to predict mutant HIV-1 proteases capable of cleaving a new target
substrate peptide, different from the natural targets of HIV-1 protease. The
obtained in silico mutant enzymes were analyzed in terms of cleavability and
specificity towards the target peptide using the energy-only methodology. We
found two mutant proteases as best candidates for specificity and cleavability
towards the target sequence
A Computational Methodology to Screen Activities of Enzyme Variants
We present a fast computational method to efficiently screen enzyme activity.
In the presented method, the effect of mutations on the barrier height of an
enzyme-catalysed reaction can be computed within 24 hours on roughly 10
processors. The methodology is based on the PM6 and MOZYME methods as
implemented in MOPAC2009, and is tested on the first step of the amide
hydrolysis reaction catalyzed by Candida Antarctica lipase B (CalB) enzyme. The
barrier heights are estimated using adiabatic mapping and are shown to give
barrier heights to within 3kcal/mol of B3LYP/6-31G(d)//RHF/3-21G results for a
small model system. Relatively strict convergence criteria
(0.5kcal/(mol{\AA})), long NDDO cutoff distances within the MOZYME method
(15{\AA}) and single point evaluations using conventional PM6 are needed for
reliable results. The generation of mutant structure and subsequent setup of
the semiempirical calculations are automated so that the effect on barrier
heights can be estimated for hundreds of mutants in a matter of weeks using
high performance computing
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