9,081 research outputs found
Refining interaction search through signed iterative Random Forests
Advances in supervised learning have enabled accurate prediction in
biological systems governed by complex interactions among biomolecules.
However, state-of-the-art predictive algorithms are typically black-boxes,
learning statistical interactions that are difficult to translate into testable
hypotheses. The iterative Random Forest algorithm took a step towards bridging
this gap by providing a computationally tractable procedure to identify the
stable, high-order feature interactions that drive the predictive accuracy of
Random Forests (RF). Here we refine the interactions identified by iRF to
explicitly map responses as a function of interacting features. Our method,
signed iRF, describes subsets of rules that frequently occur on RF decision
paths. We refer to these rule subsets as signed interactions. Signed
interactions share not only the same set of interacting features but also
exhibit similar thresholding behavior, and thus describe a consistent
functional relationship between interacting features and responses. We describe
stable and predictive importance metrics to rank signed interactions. For each
SPIM, we define null importance metrics that characterize its expected behavior
under known structure. We evaluate our proposed approach in biologically
inspired simulations and two case studies: predicting enhancer activity and
spatial gene expression patterns. In the case of enhancer activity, s-iRF
recovers one of the few experimentally validated high-order interactions and
suggests novel enhancer elements where this interaction may be active. In the
case of spatial gene expression patterns, s-iRF recovers all 11 reported links
in the gap gene network. By refining the process of interaction recovery, our
approach has the potential to guide mechanistic inquiry into systems whose
scale and complexity is beyond human comprehension
Evolutionary Multi-Objective Design of SARS-CoV-2 Protease Inhibitor Candidates
Computational drug design based on artificial intelligence is an emerging
research area. At the time of writing this paper, the world suffers from an
outbreak of the coronavirus SARS-CoV-2. A promising way to stop the virus
replication is via protease inhibition. We propose an evolutionary
multi-objective algorithm (EMOA) to design potential protease inhibitors for
SARS-CoV-2's main protease. Based on the SELFIES representation the EMOA
maximizes the binding of candidate ligands to the protein using the docking
tool QuickVina 2, while at the same time taking into account further objectives
like drug-likeliness or the fulfillment of filter constraints. The experimental
part analyzes the evolutionary process and discusses the inhibitor candidates.Comment: 15 pages, 7 figures, submitted to PPSN 202
Measuring the energy landscape roughness and the transition state location of biomolecules using single molecule mechanical unfolding experiments
Single molecule mechanical unfolding experiments are beginning to provide
profiles of the complex energy landscape of biomolecules. In order to obtain
reliable estimates of the energy landscape characteristics it is necessary to
combine the experimental measurements with sound theoretical models and
simulations. Here, we show how by using temperature as a variable in mechanical
unfolding of biomolecules in laser optical tweezer or AFM experiments the
roughness of the energy landscape can be measured without making any
assumptions about the underlying reaction oordinate. The efficacy of the
formalism is illustrated by reviewing experimental results that have directly
measured roughness in a protein-protein complex. The roughness model can also
be used to interpret experiments on forced-unfolding of proteins in which
temperature is varied. Estimates of other aspects of the energy landscape such
as free energy barriers or the transition state (TS) locations could depend on
the precise model used to analyze the experimental data. We illustrate the
inherent difficulties in obtaining the transition state location from loading
rate or force-dependent unfolding rates. Because the transition state moves as
the force or the loading rate is varied it is in general difficult to invert
the experimental data unless the curvature at the top of the one dimensional
free energy profile is large, i.e the barrier is sharp. The independence of the
TS location on force holds good only for brittle or hard biomolecules whereas
the TS location changes considerably if the molecule is soft or plastic. We
also comment on the usefulness of extension of the molecule as a surrogate
reaction coordinate especially in the context of force-quench refolding of
proteins and RNA.Comment: 44 pages, 7 figure
Onsager-Machlup action-based path sampling and its combination with replica exchange for diffusive and multiple pathways
For sampling multiple pathways in a rugged energy landscape, we propose a
novel action-based path sampling method using the Onsager-Machlup action
functional. Inspired by the Fourier-path integral simulation of a quantum
mechanical system, a path in Cartesian space is transformed into that in
Fourier space, and an overdamped Langevin equation is derived for the Fourier
components to achieve a canonical ensemble of the path at a finite temperature.
To avoid "path trapping" around an initially guessed path, the path sampling
method is further combined with a powerful sampling technique, the replica
exchange method. The principle and algorithm of our method is numerically
demonstrated for a model two-dimensional system with a bifurcated potential
landscape. The results are compared with those of conventional transition path
sampling and the equilibrium theory, and the error due to path discretization
is also discussed.Comment: 20 pages, 5 figures, submitted to J. Chem. Phy
- …