37 research outputs found
Metadynamics with adaptive Gaussians
Metadynamics is an established sampling method aimed at reconstructing the
free-energy surface relative to a set of appropriately chosen collective
variables. In standard metadynamics the free-energy surface is filled by the
addition of Gaussian potentials of pre-assigned and typically diagonal
covariance. Asymptotically the free-energy surface is proportional to the bias
deposited. Here we consider the possibility of using Gaussians whose variance
is adjusted on the fly to the local properties of the free-energy surface. We
suggest two different prescriptions: one is based on the local diffusivity and
the other on the local geometrical properties. We further examine the problem
of extracting the free-energy surface when using adaptive Gaussians. We show
that the standard relation between the bias and the free energy does not hold.
In the limit of narrow Gaussians an explicit correction can be evaluated. In
the general case we propose to use instead a relation between bias and free
energy borrowed from umbrella sampling. This relation holds for all kinds of
incrementally deposited bias. We illustrate on the case of alanine dipeptide
the advantage of using adaptive Gaussians in conjunction with the new
free-energy estimator both in terms of accuracy and speed of convergence.Comment: Reprinted (adapted) with permission from J. Chem. Theory Comput.,
DOI: 10.1021/ct3002464. Copyright (2012) American Chemical Societ
PLUMED: a portable plugin for free-energy calculations with molecular dynamics
Here we present a program aimed at free-energy calculations in molecular
systems. It consists of a series of routines that can be interfaced with the
most popular classical molecular dynamics (MD) codes through a simple patching
procedure. This leaves the possibility for the user to exploit many different
MD engines depending on the system simulated and on the computational resources
available. Free-energy calculations can be performed as a function of many
collective variables, with a particular focus on biological problems, and using
state-of-the-art methods such as metadynamics, umbrella sampling and
Jarzynski-equation based steered MD. The present software, written in ANSI-C
language, can be easily interfaced with both fortran and C/C++ codes.Comment: to be submitted to Computer Physics Communication
A Catalytic Mechanism for Cysteine N-Terminal Nucleophile Hydrolases, as Revealed by Free Energy Simulations
The N-terminal nucleophile (Ntn) hydrolases are a superfamily of enzymes specialized in the hydrolytic cleavage of amide bonds. Even though several members of this family are emerging as innovative drug targets for cancer, inflammation, and pain, the processes through which they catalyze amide hydrolysis remains poorly understood. In particular, the catalytic reactions of cysteine Ntn-hydrolases have never been investigated from a mechanistic point of view. In the present study, we used free energy simulations in the quantum mechanics/molecular mechanics framework to determine the reaction mechanism of amide hydrolysis catalyzed by the prototypical cysteine Ntn-hydrolase, conjugated bile acid hydrolase (CBAH). The computational analyses, which were confirmed in water and using different CBAH mutants, revealed the existence of a chair-like transition state, which might be one of the specific features of the catalytic cycle of Ntn-hydrolases. Our results offer new insights on Ntn-mediated hydrolysis and suggest possible strategies for the creation of therapeutically useful inhibitors
Insights into LigandâProtein Binding from Local Mechanical Response
Computational studies of ligandâprotein binding are crucial for properly designing novel compounds of potential pharmacological interest. In this respect, researchers are increasingly interested in steered molecular dynamics for ligandâprotein binding and unbinding studies. In particular, it has been suggested that analyzing the work profiles along the ligandâprotein undocking paths could be fruitful. Here, we propose that small portions of work profiles, termed âlocal mechanical responsesâ of the system to a steering force, could serve as a universal measure for capturing relevant information about the system under investigation. Specifically, we first collected a high number of steering trajectories using two biological systems of increasing complexity (i.e., alanine dipeptide and (R)-roscovitine/CDK5 complex). Then, we devised a novel postprocessing tool to be applied to the local mechanical responses, to extract structural information related to the biological processes under investigation. Despite the out-of-equilibrium character of the trajectories, the analysis carried out on the work profiles provided pivotal information about the investigated biological processes. This could eventually be applied to drug design
Ligand-Induced Modulation of the Free-Energy Landscape of G Protein-Coupled Receptors Explored by Adaptive Biasing Techniques
Extensive experimental information supports the formation of ligand-specific conformations of G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity for signaling pathways. Taking advantage of the recently published inactive and active crystal structures of GPCRs, we have implemented an all-atom computational strategy that combines different adaptive biasing techniques to identify ligand-specific conformations along pre-determined activation pathways. Using the prototypic GPCR ÎČ2-adrenergic receptor as a suitable test case for validation, we show that ligands with different efficacies (either inverse agonists, neutral antagonists, or agonists) modulate the free-energy landscape of the receptor by shifting the conformational equilibrium towards active or inactive conformations depending on their elicited physiological response. Notably, we provide for the first time a quantitative description of the thermodynamics of the receptor in an explicit atomistic environment, which accounts for the receptor basal activity and the stabilization of different active-like states by differently potent agonists. Structural inspection of these metastable states reveals unique conformations of the receptor that may have been difficult to retrieve experimentally
Astrophysics with the Laser Interferometer Space Antenna
Laser Interferometer Space Antenna (LISA) will be a transformative experiment for gravitational wave astronomy as it will offer unique opportunities to address many key astrophysical questions in a completely novel way. The synergy with ground-based and other space-based instruments in the electromagnetic domain, by enabling multi-messenger observations, will add further to the discovery potential of LISA. The next decade is crucial to prepare the astrophysical community for LISA's first observations. This review outlines the extensive landscape of astrophysical theory, numerical simulations, and astronomical observations that are instrumental for modeling and interpreting the upcoming LISA datastream. To this aim, the current knowledge in three main source classes for LISA is reviewed: ultra-compact stellar-mass binaries, massive black hole binaries, and extreme or intermediate mass ratio inspirals. The relevant astrophysical processes and the established modeling techniques are summarized. Likewise, open issues and gaps in our understanding of these sources are highlighted, along with an indication of how LISA could help make progress in the different areas. New research avenues that LISA itself, or its joint exploitation with studies in the electromagnetic domain, will enable, are also illustrated. Improvements in modeling and analysis approaches, such as the combination of numerical simulations and modern data science techniques, are discussed. This review is intended to be a starting point for using LISA as a new discovery tool for understanding our Universe
The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase
The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray
spectrometer, studied since 2015 for flying in the mid-30s on the Athena space
X-ray Observatory, a versatile observatory designed to address the Hot and
Energetic Universe science theme, selected in November 2013 by the Survey
Science Committee. Based on a large format array of Transition Edge Sensors
(TES), it aims to provide spatially resolved X-ray spectroscopy, with a
spectral resolution of 2.5 eV (up to 7 keV) over an hexagonal field of view of
5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement
Review (SRR) in June 2022, at about the same time when ESA called for an
overall X-IFU redesign (including the X-IFU cryostat and the cooling chain),
due to an unanticipated cost overrun of Athena. In this paper, after
illustrating the breakthrough capabilities of the X-IFU, we describe the
instrument as presented at its SRR, browsing through all the subsystems and
associated requirements. We then show the instrument budgets, with a particular
emphasis on the anticipated budgets of some of its key performance parameters.
Finally we briefly discuss on the ongoing key technology demonstration
activities, the calibration and the activities foreseen in the X-IFU Instrument
Science Center, and touch on communication and outreach activities, the
consortium organisation, and finally on the life cycle assessment of X-IFU
aiming at minimising the environmental footprint, associated with the
development of the instrument. Thanks to the studies conducted so far on X-IFU,
it is expected that along the design-to-cost exercise requested by ESA, the
X-IFU will maintain flagship capabilities in spatially resolved high resolution
X-ray spectroscopy, enabling most of the original X-IFU related scientific
objectives of the Athena mission to be retained. (abridged).Comment: 48 pages, 29 figures, Accepted for publication in Experimental
Astronomy with minor editin
The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase
The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory. Athena is a versatile observatory designed to address the Hot and Energetic Universe science theme, as selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), X-IFU aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over a hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR (i.e. in the course of its preliminary definition phase, so-called B1), browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters, such as the instrument efficiency, spectral resolution, energy scale knowledge, count rate capability, non X-ray background and target of opportunity efficiency. Finally, we briefly discuss the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, touch on communication and outreach activities, the consortium organisation and the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. The X-IFU will be provided by an international consortium led by France, The Netherlands and Italy, with ESA member state contributions from Belgium, Czech Republic, Finland, Germany, Poland, Spain, Switzerland, with additional contributions from the United States and Japan.The French contribution to X-IFU is funded by CNES, CNRS and CEA. This work has been also supported by ASI (Italian Space Agency) through the Contract 2019-27-HH.0, and by the ESA (European Space Agency) Core Technology Program (CTP) Contract No. 4000114932/15/NL/BW and the AREMBES - ESA CTP No.4000116655/16/NL/BW. This publication is part of grant RTI2018-096686-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by âERDF A way of making Europeâ. This publication is part of grant RTI2018-096686-B-C21 and PID2020-115325GB-C31 funded by MCIN/AEI/10.13039/501100011033
Metadynamics with Adaptive Gaussians
Metadynamics is an established sampling method aimed
at reconstructing
the free-energy surface relative to a set of appropriately chosen
collective variables. In standard metadynamics, the free-energy surface
is filled by the addition of Gaussian potentials of preassigned and
typically diagonal covariance. Asymptotically the free-energy surface
is proportional to the bias deposited. Here, we consider the possibility
of using Gaussians whose variance is adjusted on the fly to the local
properties of the free-energy surface. We suggest two different prescriptions:
one is based on the local diffusivity and the other on the local geometrical
properties. We further examine the problem of extracting the free-energy
surface when using adaptive Gaussians. We show that the standard relation
between the bias and the free energy does not hold. In the limit of
narrow Gaussians an explicit correction can be evaluated. In the general
case, we propose to use instead a relation between bias and free energy
borrowed from umbrella sampling. This relation holds for all kinds
of incrementally deposited bias. We illustrate on the case of alanine
dipeptide the advantage of using adaptive Gaussians in conjunction
with the new free-energy estimator both in terms of accuracy and speed
of convergence
Water quality survey of tubewells in Hyderabad district
In Asghar, Muhammad Nadeem; Zhu, Zhongping; Sohag, Mumtaz Ahmed; Lashari, Bhakshal. Assessment of hydro-geological potential of skimming wells in the Lower Indus Basin of Pakistan. Lahore, Pakistan: IWM