982 research outputs found
CHARMM: The biomolecular simulation program
CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983. © 2009 Wiley Periodicals, Inc.J Comput Chem, 2009.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63074/1/21287_ftp.pd
RE-EDS Using GAFF Topologies: Application to Relative Hydration Free-Energy Calculations for Large Sets of Molecules
Free-energy differences between pairs of end-states can be estimated based on
molecular dynamics (MD) simulations using standard pathway-dependent methods
such as thermodynamic integration (TI), free-energy perturbation, or Bennett's
acceptance ratio. Replica-exchange enveloping distribution sampling (RE-EDS),
on the other hand, allows for the sampling of multiple end-states in a single
simulation without the specification of any pathways. In this work, we use the
RE-EDS method as implemented in GROMOS together with generalized AMBER force
field (GAFF) topologies, converted to a GROMOS-compatible format with a newly
developed GROMOS++ program amber2gromos, to compute relative hydration free
energies for a series of benzene derivatives. The results obtained with RE-EDS
are compared to the experimental data as well as calculated values from the
literature. In addition, the estimated free-energy differences in water and in
vacuum are compared to values from TI calculations carried out with GROMACS.
The hydration free energies obtained using RE-EDS for multiple molecules are
found to be in good agreement with both the experimental data and the results
calculated using other free-energy methods. While all considered free-energy
methods delivered accurate results, the RE-EDS calculations required the least
amount of total simulation time. This work serves as a validation for the use
of GAFF topologies with the GROMOS simulation package and the RE-EDS approach.
Furthermore, the performance of RE-EDS for a large set of 28 end-states is
assessed with promising results
Modeling the Binding of Neurotransmitter Transporter Inhibitors with Molecular Dynamics and Free Energy Calculations
The monoamine transporter (MAT) proteins responsible for the reuptake of the neurotransmitter substrates, dopamine, serotonin, and norepinephrine, are drug targets for the treatment of psychiatric disorders including depression, anxiety, and attention deficit hyperactivity disorder. Small molecules that inhibit these proteins can serve as useful therapeutic agents. However, some dopamine transporter (DAT) inhibitors, such as cocaine and methamphetamine, are highly addictive and abusable. Efforts have been made to develop small molecules that will inhibit the transporters and elucidate specific binding site interactions. This work provides knowledge of molecular interactions associated with MAT inhibitors by offering an atomistic perspective that can guide designs of new pharmacotherapeutics with enhanced activity.
The work described herein evaluates intermolecular interactions using computational methods to reveal the mechanistic detail of inhibitors binding in the DAT. Because cocaine recognizes the extracellular-facing or outward-facing (OF) DAT conformation and benztropine recognizes the intracellular-facing or inward-facing (IF) conformation, it was postulated that behaviorally “typical” (abusable, locomotor psychostimulant) inhibitors stabilize the OF DAT and “atypical” (little or no abuse potential) inhibitors favor IF DAT. Indeed, behaviorally-atypical cocaine analogs have now been shown to prefer the OF DAT conformation. Specifically, the binding interactions of two cocaine analogs, LX10 and LX11, were studied in the OF DAT using molecular dynamics simulations. LX11 was able to interact with residues of transmembrane helix 8 and bind in a fashion that allowed for hydration of the primary binding site (S1) from the intracellular space, thus impacting the intracellular interaction network capable of regulating conformational transitions in DAT.
Additionally, a novel serotonin transporter (SERT) inhibitor previously discovered through virtual screening at the SERT secondary binding site (S2) was studied. Intermolecular interactions between SM11 and SERT have been assessed using binding free energy calculations to predict the ligand-binding site and optimize ligand-binding interactions. Results indicate the addition of atoms to the 4-chlorobenzyl moiety were most energetically favorable.
The simulations carried out in DAT and SERT were supported by experimental results. Furthermore, the co-crystal structures of DAT and SERT share similar ligand-binding interactions with the homology models used in this study
What to Make of Zero: Resolving the Statistical Noise from Conformational Reorganization in Alchemical Binding Free Energy Estimates with Metadynamics Sampling
We introduce the self-Relative Binding Free Energy (self-RBFE) approach to
evaluate the intrinsic statistical variance of dual-topology alchemical binding
free energy estimators. The self-RBFE is the relative binding free energy
between a ligand and a copy of the same ligand, and its true value is zero.
Nevertheless, because the two copies of the ligand move independently, the
self-RBFE value produced by a finite-length simulation fluctuates and can be
used to measure the variance of the model. The results of this validation
provide evidence that a significant fraction of the errors observed in
benchmark studies reflect the statistical fluctuations of unconverged estimates
rather than the models' accuracy. Furthermore, we find that ligand
reorganization is a significant contributing factor to the statistical variance
of binding free energy estimates and that metadynamics-accelerated
conformational sampling of torsional degrees of freedom of the ligand can
drastically reduce the time to convergence
Reproducibility of Free Energy Calculations Across Different Molecular Simulation Software
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<p>Alchemical free energy calculations are an increasingly important modern simulation
technique. Contemporary molecular simulation software such as AMBER, CHARMM,
GROMACS and SOMD include support for the method. Implementation details vary
among those codes but users expect reliability and reproducibility, i.e. for a given molec-
ular model and set of forcefield parameters, comparable free energy should be obtained within statistical bounds regardless of the code used. Relative alchemical free energy
(RAFE) simulation is increasingly used to support molecule discovery projects, yet the
reproducibility of the methodology has been less well tested than its absolute counter-
part. Here we present RAFE calculations of hydration free energies for a set of small
organic molecules and demonstrate that free energies can be reproduced to within about
0.2 kcal/mol with aforementioned codes. Achieving this level of reproducibility requires
considerable attention to detail and package–specific simulation protocols, and no uni-
versally applicable protocol emerges. The benchmarks and protocols reported here
should be useful for the community to validate new and future versions of software for
free energy calculations.</p></div></div></div
Conformations and coherences in structure determination by ultrafast electron diffraction
In this article we consider consequences of spatial coherences and conformations in diffraction of (macro)molecules with different potential energy landscapes. The emphasis is on using this understanding to extract structural and temporal information from diffraction experiments. The theoretical analysis of structural interconversions spans an increased range of complexity, from small hydrocarbons to proteins. For each molecule considered, we construct the potential energy landscape and assess the characteristic conformational states available. For molecules that are quasiharmonic in the vicinity of energy minima, we find that the distinct conformer model is sufficient even at high temperatures. If, however, the energy surface is either locally flat around the minima or the molecule includes many degrees of conformational freedom, a Boltzmann ensemble must be used, in what we define as the pseudoconformer approach, to reproduce the diffraction. For macromolecules with numerous energy minima, the ensemble of hundreds of structures is considered, but we also utilize the concept of the persistence length to provide information on orientational coherence and its use to assess the degree of resonance contribution to diffraction. It is shown that the erosion of the resonant features in diffraction which are characteristic of some quasiperiodic structural motifs can be exploited in experimental studies of conformational interconversions triggered by a laser-induced temperature jump
Accelerate sampling in atomistic energy landscapes using topology-based coarse-grained models
We describe a multiscale enhanced sampling (MSES) method where efficient topology-based coarse-grained models are coupled with all-atom ones to enhance the sampling of atomistic protein energy landscape. The bias from the coupling is removed by Hamiltonian replica exchange, thus allowing one to benefit simultaneously from faster transitions of coarse-grained modeling and accuracy of atomistic force fields. The method is demonstrated by calculating the conformational equilibria of several small but nontrivial β-hairpins with varied stabilities
Performance and Analysis of the Alchemical Transfer Method for Binding Free Energy Predictions of Diverse Ligands
The Alchemical Transfer Method (ATM) is herein validated against the relative
binding free energies of a diverse set of protein-ligand complexes. We employed
a streamlined setup workflow, a bespoke force field, and the AToM-OpenMM
software to compute the relative binding free energies (RBFE) of the benchmark
set prepared by Schindler and collaborators at Merck KGaA. This benchmark set
includes examples of standard small R-group ligand modifications as well as
more challenging scenarios, such as large R-group changes, scaffold hopping,
formal charge changes, and charge-shifting transformations. The novel
coordinate perturbation scheme and a dual-topology approach of ATM address some
of the challenges of single-topology alchemical relative binding free energy
methods. Specifically, ATM eliminates the need for splitting electrostatic and
Lennard-Jones interactions, atom mapping, defining ligand regions, and
post-corrections for charge-changing perturbations. Thus, ATM is simpler and
more broadly applicable than conventional alchemical methods, especially for
scaffold-hopping and charge-changing transformations. Here, we performed well
over 500 relative binding free energy calculations for eight protein targets
and found that ATM achieves accuracy comparable to existing state-of-the-art
methods, albeit with larger statistical fluctuations. We discuss insights into
specific strengths and weaknesses of the ATM method that will inform future
deployments. This study confirms that ATM is applicable as a production tool
for relative binding free energy (RBFE) predictions across a wide range of
perturbation types within a unified, open-source framework
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