64,517 research outputs found
Spatial chemical distance based on atomic property fields
Similarity of compound chemical structures often leads to close pharmacological profiles, including binding to the same protein targets. The opposite, however, is not always true, as distinct chemical scaffolds can exhibit similar pharmacology as well. Therefore, relying on chemical similarity to known binders in search for novel chemicals targeting the same protein artificially narrows down the results and makes lead hopping impossible. In this study we attempt to design a compound similarity/distance measure that better captures structural aspects of their pharmacology and molecular interactions. The measure is based on our recently published method for compound spatial alignment with atomic property fields as a generalized 3D pharmacophoric potential. We optimized contributions of different atomic properties for better discrimination of compound pairs with the same pharmacology from those with different pharmacology using Partial Least Squares regression. Our proposed similarity measure was then tested for its ability to discriminate pharmacologically similar pairs from decoys on a large diverse dataset of 115 protein–ligand complexes. Compared to 2D Tanimoto and Shape Tanimoto approaches, our new approach led to improvement in the area under the receiver operating characteristic curve values in 66 and 58% of domains respectively. The improvement was particularly high for the previously problematic cases (weak performance of the 2D Tanimoto and Shape Tanimoto measures) with original AUC values below 0.8. In fact for these cases we obtained improvement in 86% of domains compare to 2D Tanimoto measure and 85% compare to Shape Tanimoto measure. The proposed spatial chemical distance measure can be used in virtual ligand screening
Machine Learning, Quantum Mechanics, and Chemical Compound Space
We review recent studies dealing with the generation of machine learning
models of molecular and solid properties. The models are trained and validated
using standard quantum chemistry results obtained for organic molecules and
materials selected from chemical space at random
First principles view on chemical compound space: Gaining rigorous atomistic control of molecular properties
A well-defined notion of chemical compound space (CCS) is essential for
gaining rigorous control of properties through variation of elemental
composition and atomic configurations. Here, we review an atomistic first
principles perspective on CCS. First, CCS is discussed in terms of variational
nuclear charges in the context of conceptual density functional and molecular
grand-canonical ensemble theory. Thereafter, we revisit the notion of compound
pairs, related to each other via "alchemical" interpolations involving
fractional nuclear chargens in the electronic Hamiltonian. We address Taylor
expansions in CCS, property non-linearity, improved predictions using reference
compound pairs, and the ounce-of-gold prize challenge to linearize CCS.
Finally, we turn to machine learning of analytical structure property
relationships in CCS. These relationships correspond to inferred, rather than
derived through variational principle, solutions of the electronic
Schr\"odinger equation
Dynamics of Current, Charge and Mass
Electricity plays a special role in our lives and life. Equations of electron
dynamics are nearly exact and apply from nuclear particles to stars. These
Maxwell equations include a special term the displacement current (of vacuum).
Displacement current allows electrical signals to propagate through space.
Displacement current guarantees that current is exactly conserved from inside
atoms to between stars, as long as current is defined as Maxwell did, as the
entire source of the curl of the magnetic field. We show how the Bohm
formulation of quantum mechanics allows easy definition of current. We show how
conservation of current can be derived without mention of the polarization or
dielectric properties of matter. Matter does not behave the way physicists of
the 1800's thought it does with a single dielectric constant, a real positive
number independent of everything. Charge moves in enormously complicated ways
that cannot be described in that way, when studied on time scales important
today for electronic technology and molecular biology. Life occurs in ionic
solutions in which charge moves in response to forces not mentioned or
described in the Maxwell equations, like convection and diffusion. Classical
derivations of conservation of current involve classical treatments of
dielectrics and polarization in nearly every textbook. Because real dielectrics
do not behave in a classical way, classical derivations of conservation of
current are often distrusted or even ignored. We show that current is conserved
exactly in any material no matter how complex the dielectric, polarization or
conduction currents are. We believe models, simulations, and computations
should conserve current on all scales, as accurately as possible, because
physics conserves current that way. We believe models will be much more
successful if they conserve current at every level of resolution, the way
physics does.Comment: Version 4 slight reformattin
Transferable atomic multipole machine learning models for small organic molecules
Accurate representation of the molecular electrostatic potential, which is
often expanded in distributed multipole moments, is crucial for an efficient
evaluation of intermolecular interactions. Here we introduce a machine learning
model for multipole coefficients of atom types H, C, O, N, S, F, and Cl in any
molecular conformation. The model is trained on quantum chemical results for
atoms in varying chemical environments drawn from thousands of organic
molecules. Multipoles in systems with neutral, cationic, and anionic molecular
charge states are treated with individual models. The models' predictive
accuracy and applicability are illustrated by evaluating intermolecular
interaction energies of nearly 1,000 dimers and the cohesive energy of the
benzene crystal.Comment: 11 pages, 6 figure
Carbon fibre tips for scanning probe microscopy based on quartz tuning fork force sensors
We report the fabrication and the characterization of carbon fibre tips for
their use in combined scanning tunnelling and force microscopy based on
piezoelectric quartz tuning fork force sensors. We find that the use of carbon
fibre tips results in a minimum impact on the dynamics of quartz tuning fork
force sensors yielding a high quality factor and consequently a high force
gradient sensitivity. This high force sensitivity in combination with high
electrical conductivity and oxidation resistance of carbon fibre tips make them
very convenient for combined and simultaneous scanning tunnelling microscopy
and atomic force microscopy measurements. Interestingly, these tips are quite
robust against occasionally occurring tip crashes. An electrochemical
fabrication procedure to etch the tips is presented that produces a sub-100 nm
apex radius in a reproducible way which can yield high resolution images.Comment: 14 pages, 10 figure
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