152 research outputs found
Estimation of the infinitesimal generator by square-root approximation
For the analysis of molecular processes, the estimation of time-scales, i.e.,
transition rates, is very important. Estimating the transition rates between
molecular conformations is -- from a mathematical point of view -- an invariant
subspace projection problem. A certain infinitesimal generator acting on
function space is projected to a low-dimensional rate matrix. This projection
can be performed in two steps. First, the infinitesimal generator is
discretized, then the invariant subspace is approxi-mated and used for the
subspace projection. In our approach, the discretization will be based on a
Voronoi tessellation of the conformational space. We will show that the
discretized infinitesimal generator can simply be approximated by the geometric
average of the Boltzmann weights of the Voronoi cells. Thus, there is a direct
correla-tion between the potential energy surface of molecular structures and
the transition rates of conformational changes. We present results for a
2d-diffusion process and Alanine dipeptide
Publisher’s Note: “Density-based cluster algorithms for the identification of core sets” [J. Chem. Phys. 145, 164104 (2016)]
Original Article: J. Chem. Phys. 145, 164104 (2016) This article was
originally published online on 26 October 2016 with an error in the second
author’s name. “Bettina G. Lemke” should be “Bettina G. Keller.” AIP
Publishing apologizes for this error. All online versions of the article were
corrected on 27 October 2016; the article is correct as it appears in the
printed version of the journal
GROMACS Stochastic Dynamics and BAOAB are equivalent configurational sampling algorithms
Two of the most widely used Langevin integrators for molecular dynamics
simulations are the GROMACS Stochastic Dynamics (GSD) integrator and the
splitting method BAOAB. We show that the GROMACS Stochastic Dynamics integrator
is equal to the less frequently used splitting method BAOA. It immediately
follows that GSD and BAOAB sample the same configurations and have the same
high configurational accuracy. Our numerical results indicate that GSD/BAOA has
higher kinetic accuracy than BAOAB
Path probability ratios for Langevin dynamics -- exact and approximate
Path reweighting is a principally exact method to estimate dynamic properties
from biased simulations - provided that the path probability ratio matches the
stochastic integrator used in the simulation. Previously reported path
probability ratios match the Euler-Maruyama scheme for overdamped Langevin
dynamics. Since MD simulations use Langevin dynamics rather than overdamped
Langevin dynamics, this severely impedes the application of path reweighting
methods. Here, we derive the path probability ratio for Langevin dynamics
propagated by a variant of the Langevin Leapfrog integrator. This new path
probability ratio allows for exact reweighting of Langevin dynamics propagated
by this integrator. We also show that a previously derived approximate path
probability ratio differs from the exact only by
, and thus yields highly accurate dynamic
reweighting results. ( is the integration time step, is the
collision rate.) The results are tested and the efficiency of path-reweighting
is explored using butane as an example
Grid-based state space exploration for molecular binding
Binding processes are difficult to sample with molecular-dynamics (MD)
simulations. In particular, the state space exploration is often incomplete.
Evaluating the molecular interaction energy on a grid circumvents this problem
but is heavily limited by state space dimensionality. Here, we make the first
steps towards a low-dimensional grid-based model of molecular binding. We
discretise the state space of relative positions and orientations of the two
molecules under the rigid body assumption.The corresponding program is
published as the Python package molgri. For the rotational component of the
grids, we test algorithms based on Euler angles, polyhedra and quaternions, of
which the polyhedra-based are the most uniform. The program outputs a sequence
of molecular structures that can be easily processed by standard MD programs to
calculate grid point energies. We demonstrate the grid-based approach on two
molecular systems: a water dimer and a coiled-coil protein interacting with a
chloride anion. For the second system we relax the rigid-body assumption and
improve the accuracy of the grid point energies by an energy minimisation. In
both cases, oriented bonding patterns and energies confirm expectations from
chemical intuition and MD simulations. We also demonstrate how analysis of
energy contributions on a grid can be performed and demonstrate that
electrostatically-driven association is sufficiently resolved by point-energy
calculations. Overall, grid-based models of molecular binding are potentially a
powerful complement to molecular sampling approaches, and we see the potential
to expand the method to quantum chemistry and flexible docking applications.Comment: 13 pages, 7 figure
A review of Girsanov Reweighting and of Square Root Approximation for building molecular Markov State Models
Dynamical reweighting methods permit to estimate kinetic observables of a
stochastic process governed by a target potential from
trajectories that have been generated at a different potential . In this
article, we present Girsanov reweighting and Square Root Approximation (SqRA):
the first method reweights path probabilities exploiting the Girsanov theorem
and can be applied to Markov State Models (MSMs) to reweight transition
probabilities; the second method was originally developed to discretize the
Fokker-Planck operator into a transition rate matrix, but here we implement it
into a reweighting scheme for transition rates. We begin by reviewing the
theoretical background of the methods, then present two applications relevant
to Molecular Dynamics (MD), highlighting their strengths and weaknesses
Markov models from the square root approximation of the Fokker–Planck equation: calculating the grid-dependent flux
Abstract
Molecular dynamics (MD) are extremely complex, yet understanding the slow components of
their dynamics is essential to understanding their macroscopic properties. To achieve this, one
models the MD as a stochastic process and analyses the dominant eigenfunctions of the
associated Fokker–Planck operator, or of closely related transfer operators. So far, the
calculation of the discretized operators requires extensive MD simulations. The square-root
approximation of the Fokker–Planck equation is a method to calculate transition rates as a
ratio of the Boltzmann densities of neighboring grid cells times a flux, and can in principle be
calculated without a simulation. In a previous work we still used MD simulations to determine
the flux. Here, we propose several methods to calculate the exact or approximate flux for
various grid types, and thus estimate the rate matrix without a simulation. Using model
potentials we test computational efficiency of the methods, and the accuracy with which they
reproduce the dominant eigenfunctions and eigenvalues. For these model potentials, rate
matrices with up to O(106) states can be obtained within seconds on a single
high-performance compute server if regular grids are used
How chromophore labels shape the structure and dynamics of a peptide hydrogel
Biocompatible and functionalizable hydrogels have a wide range of (potential)
medicinal applications. In contrast to conventional hydrogels formed by
interconnected or interlocked polymer chains, self-assembled hydrogels form
from small building blocks like short peptide chains. This has the advantage
that the building blocks can be functionalized separately and then mixed to
obtain the desired properties. However, the hydrogelation process for these
systems, especially those with very low polymer weight percentage (< 1 wt%), is
not well understood, and therefore it is hard to predict whether a given
molecular building block will self-assemble into a hydrogel. This severely
hinders the rational design of self-assembled hydrogels. In this study, we
demonstrate the impact of an N-terminal chromophore label amino-benzoic acid on
the self-assembly and rheology of hydrogel hFF03 (hydrogelating, fibril
forming) using molecular dynamics simulations, which self-assembles into
{\alpha}-helical coiled-coils. We find that the chromophore and even its
specific regioisomers have a significant influence on the microscopic structure
and dynamics of the self-assembled fibril, and on the macroscopic mechanical
properties. This is because the chromophore influences the possible
salt-bridges which form and stabilize the fibril formation. Furthermore we find
that the solvation shell fibrils by itself cannot explain the viscoelasticity
of hFF03 hydrogels. Our atomistic model of the hFF03 fibril formation enables a
more rational design of these hydrogels. In particular, altering the N-terminal
chromophore emergesas a design strategy to tune the mechanic properties of
these self-assembled peptide hydrogels.Comment: 15 pages, 15 including appendi
The occurrence of ansamers in the synthesis of cyclic peptides
α-Amanitin is a bicyclic octapeptide composed of a macrolactam with a tryptathionine cross-link forming a handle. Previously, the occurrence of isomers of amanitin, termed atropisomers has been postulated. Although the total synthesis of α-amanitin has been accomplished this aspect still remains unsolved. We perform the synthesis of amanitin analogs, accompanied by in-depth spectroscopic, crystallographic and molecular dynamics studies. The data unambiguously confirms the synthesis of two amatoxin-type isomers, for which we propose the term ansamers. The natural structure of the P-ansamer can be ansa-selectively synthesized using an optimized synthetic strategy. We believe that the here described terminology does also have implications for many other peptide structures, e.g. norbornapeptides, lasso peptides, tryptorubins and others, and helps to unambiguously describe conformational isomerism of cyclic peptides
A Formylglycine-Peptide for the Site-Directed Identification of Phosphotyrosine-Mimetic Fragments
Discovery of protein-binding fragments for precisely defined binding sites is an unmet challenge to date. Herein, formylglycine is investigated as a molecular probe for the sensitive detection of fragments binding to a spatially defined protein site . Formylglycine peptide 3 was derived from a phosphotyrosine-containing peptide substrate of protein tyrosine phosphatase PTP1B by replacing the phosphorylated amino acid with the reactive electrophile. Fragment ligation with formylglycine occurred in situ in aqueous physiological buffer. Structures and kinetics were validated by NMR spectroscopy. Screening and hit validation revealed fluorinated and non-fluorinated hit fragments being able to replace the native phosphotyrosine residue. The formylglycine probe identified low-affinity fragments with high spatial resolution as substantiated by molecular modelling. The best fragment hit, 4-amino-phenyl-acetic acid, was converted into a cellularly active, nanomolar inhibitor of the protein tyrosine phosphatase SHP2
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