Free Energy Calculations in Amber
Thermodynamic Integration using soft
core potentials
Thermodynamic Integration (TI) is a technique used to compute relative binding free enegy.
This tutorial uses TI on two simple ligands, benzene and phenol, and their binding with the T4-lysozyme
mutant L99A.
Advanced Thermodynamic Integration
Using ACES
This tutorial calculates the relative binding free energies between two
inhibitors bound to the the human THr160-phospho CDK2/cyclin A protein. The
methodology employed is a little more sophisticated that the standard TI.
pKa Calculations using Thermodynamic
Integration
This tutorial reproduces the calculation of
the pKa value of the ASP residue in the protein thioredoxin
as described in
the following paper:
Simonson, T., Carlsson, J., Case, D.A., "Proton Binding to Proteins:
pKa Calculations with Explicit and Implicit Solvent Models", JACS
2004, 126, pp 4167-4180. By Ross Walker and Mike Crowley.
Molecular Mechanics with a Poisson Boltzmann/Surface Area solvent:MM-PBSA
This tutorial provides a step by step explanation of using the
mm_pbsa script to calculate the binding
energy of the RAS-RAF protein complex. It also includes instructions on
using the mmpbsa_py script to perform these
calculations as well.
(Japanese
translation) By Ross Walker and Thomas Steinbrecher.
Umbrella Sampling:
A Potential of Mean Force in alanine dipeptide Phi/Psi Rotation
In this tutorial we will learn how to
use the AMBER software coupled with the Weighted
Histogram Analysis Method (WHAM) of Alan Grossfield
to generate potentials of mean force. Often one
might want to know what the free energy profile is
along a specific reaction coordinate. Such a profile is known
as a potential of mean force and it can
be very useful for identifying transition states,
intermediates as well as
the relative stabilities of the end points.
At first thought one might think
that you could generate a free energy along a specific
reaction coordinate by
just running an MD simulation and then looking at the
probabilities of the
states sampled. However, often the energy barrier
of interest is many times
the size of kbT and so the MD simulation
will either remain in the
local minimum it started in or cross to
different minima but very very rarely
sample the transition state. Umbrella sampling
offers a way to effectively
force the system to move through a transition
state and reaction pathway that
chemical knowledge of the system under
study suggests is important. By Ross Walker and Thomas Steinbrecher.
Umbrella Sampling: Transferring methanol through a membrane
This tutorial illustrates how
to use the fxyz capability to carry out umbrella sampling in
specific directions.
It uses the AMBER16 center-of-mass (COM) umbrella restraint
code to determine the free energy of transfer profile for a methanol
molecule through a DMPC membrane bilayer. The methanol molecule is first
pulled from the center of the membrane out into the water phase. From
the pulling step, we extract starting positions with methanol at 0, 2,
4, ..., 32 A from the membrane center. We run windows with methanol
restrained at each of these positions. From the fluctuation in the
z-position, we can construct the free energy profile using WHAM.
Finally, we use the same information to derive the z-diffusion and
z-resistance profiles and an estimate of the overall permeability
coefficient. By Callum Dickson.
Free Energy
Estimation for Conformers of Dialanine using EMIL
[AMBER v14 and later]
This tutorial is a walk-through of absolute free energy calculations using
EMIL. EMIL works by perturbing the "normal" atomistic representation of the
system into a model for which the free energy is exactly known, thus it is a
sort of thermodynamic integration tool. The example in this tutorial is an
estimate of the four free energy basins of the alanine dipeptide.By Joshua
T. Berryman.
Computing Binding
Enthalpy Values
In this tutorial, we will learn how to
use AMBER to compute precise binding enthalpies using explicit water
molecular dynamics simulations. Here we focus on the guest B2 binding to the
host CB7. However, while the example in this tutorial focuses on a
host-guest system, the technique is directly applicable to protein-ligand
systems although we caution that the such systems will require considerably
more sampling to converge than the host-guest system in this
tutorial. By Andrew T. Fenley and Michael K. Gilson.
Free energy
calculations with the Free Energy Workflow Tool (FEW)
This tutorial demonstrates the functionality of the Free Energy
Workflow tool FEW. Using a sample data set of inhibitors of the
protein Factor Xa it is shown how FEW can be used to easily prepare MD
simulations and binding free energy calculations by the MM-PB(GB)SA, the
linear interaction energy (LIE), and the thermodynamic integration (TI)
method for multiple ligands binding to the same receptor. FEW provides an
efficient way to setup and conduct binding free energy calculations
with AMBER. By Nadine Homeyer and Holger Gohlke.
Grid Inhomogeneous
Solvation Theory for water thermodynamics: in Factor Xa
In this tutorial we will learn how to use the
AMBER software coupled with the Grid Inhomogeneous Solvation Theory Method
(GIST) to estimate thermodynamic values for the water molecules occupying the
binding pocket of Factor Xa. Often one might want to estimate changes in
hydration which are central to correctly describe biomolecular phenomena such
as molecular recognition, drug binding, etc. However, it is difficult to
estimate precisely the thermodynamic solvation contribution in these
phenomena. By Romelia Salomon, Crystal Nguyen, Steven Ramsey,
Jonathan D. Gough, and Ross Walker.
Computing Binding
Free Energy using the Attach-Pull-Release (APR) Method
This tutorial demonstrates how to use the attach-pull-release (APR) approach
to compute the binding thermodynamics of a host-guest system with an explicit
water model. Results from binding calculations using the APR approach showed
moderate to strong correlations to the experimental measurements of
cucurbit[7]uril (CB7), octa acid (OA), tetra-endo-methyl octa-acid (TEMOA),
α- and β-cyclodextrin (α-CD and β-CD) with their guest
molecules. By Jian Yin, Niel M. Henriksen, David R. Slochower, and
Michael K. Gilson.
The Nonequilibrium
Free Energy (NFE) Toolkit for PMEMD
This tutorial introduces the Nonequilibrium Free Energy (NFE) toolkit, which
is fully functional in SANDER and partially ported to PMEMD AMBER. The
purpose of this tutorial is multifold. We review the current status of the
porting of software to PMEMD AMBER v.16, and provide suitable patches for
upgrading the toolkit to older versions of AMBER (v.14). Additionally,
patches are provided for upgrading modules not released to PMEMD AMBER v.16,
and we provide a step-by-step tutorial on how to write new collective
variables for free energy calculations. Software templates for new
collective variables are also given. Finally, a few examples of using the
new PMEMD versions of the code is provided. By Feng Pan, Mahmoud Moradi,
Christopher Roland, and
Celeste Sagui.
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