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7 Free Energy Calculations in Amber

7.1 MM-PBSA

RAS-RAF complex 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

7.2 pKa Calculations using Thermodynamic Integration

pKa thermodynamic cycleThis 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, pp4167-4180.

By Ross Walker and Mike Crowley

7.3 Thermodynamic Integration using soft core potentials

protein for Softcoring tutorialThis tutorial computes the relative binding free energy of two ligands bound to a lysozyme mutant. In three steps, you will learn about the background of soft core TI calculation, the new system setup for Amber10 or later, and how to run and analyze a short free energy calculation.

By Thomas Steinbrecher

7.4 Umbrella Sampling Example - Calculating the PMF for Alanine Dipeptide Phi/Psi Rotation

umbrella sampling toc image 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

7.5 Umbrella Sampling Example - moving methanol across a membrane

umbrella sampling toc image 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

7.6 Free Energy Estimation for Conformers of Dialanine using EMIL [AMBER v14 and later]

EMIL toc image 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

7.7 Computing Binding Enthalpy Values

Binding Enthalpy toc image 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

7.8 Free energy calculations with the Free Energy Workflow Tool (FEW)

FEW toc image
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

7.9 Analysis of water thermodynamics using Grid Inhomogeneous Solvation Theory of Factor Xa active site

GIST 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

7.10 Computing Binding Free Energy using the Attach-Pull-Release (APR) Method

APR toc image 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 & Michael K. Gilson

7.11 The Nonequilibrium Free Energy (NFE) Toolkit for PMEMD AMBER: Capabilities, Examples, and Collective Variables

NFE 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 & Celeste Sagui

"How's that for maxed out?"

Last modified: Aug 27, 2021