AMBER Archive (2000)

Subject: AMBER 6

From: Bill Ross (ross_at_cgl.ucsf.edu)
Date: Tue Jan 04 2000 - 13:46:01 CST

[note - the web site has just been updated to reflect this:]

It is with great pleasure that we announce the availability of AMBER 6.
AMBER--one of the most widely licensed molecular modeling and simulation
packages in the world--provides high powered facilities for a large number of
new simulation-based methods. Highlights of AMBER 6 include many new and
useful features, as detailed below. It is our belief that these new
features add great value to AMBER and fully justify the introduction of a
new version of the package. We hope you agree and choose to license AMBER
6. Note that funds from licensing AMBER 6 support research by the authors
of the package, and thus your fees support further development of new
features.

The academic price for licensing is the same as for AMBER 5, $400. (This
fee may be reduced or waived in special circumstances.) The industrial
price is $20,000 for new licensees and $15,000 for those who have licensed
AMBER 5.

To proceed with ordering AMBER 6, go to the AMBER web site,

  http://www.AMBER.ucsf.edu/amber

This site has much additional information, including the manual and
tutorials. To order AMBER, you can download the license agreement from
the web site, sign it, and send with an appropriate check or money order
made out to the Regents of the University of California, to Willa
Crowell (willa_at_cgl.ucsf.edu), Department of Pharmaceutical Chemistry,
University of California, San Francisco, 94143.

Overview of AMBER 6:

AMBER 6 has a number of very exciting capabilities which should prove very
powerful in structure-based ligand design and in the understanding of
structure and free energy in any complex molecular system. New methods such
as Chemical Monte Carlo/Molecular Dynamics (CMC/MD) allow the consideration
of many molecules simultaneously and are a powerful complement to more
qualitative approaches in drug design. One can imagine using DOCKing
methods to screen databases of ligands and, after reducing the number of
possible leads to leads ~100, using this method to more accurately estimate
the binding free energy for these 100 compounds. Another major development
has been the use of continuum methods combined with explicit MD and
molecular mechanics. The method of computational Alanine scanning by
Massova and Kollman (JACS, 121:8133, 1999) reflects the exciting possibility
of modeling many protein mutants at once. In the era of genomics, use of
MM-PBSA (Molecular mechanics- Poisson Bolzmann Surface Area) using molecular
dynamics should lead to more accurate protein models and, when combined with
homology modeled protein structures, should aid computer assisted design of
tight binding ligands by making the protein structure more reliable and
robust. The methodology of locally enhanced sampling (LES) has already been
shown to be very powerful in protein structure refinement (Simmerling et al,
JACS, submitted). New dynamics simulation methods to aid in ligand
design(OWFEG and PROFEC) are available in AMBER 6. As additional bonuses,
the excellent software for NMR refinement, the latest in force field models
and parameters and the capabilities to model enzyme mechanisms (Stanton et
al, JACS, 120:3448, 1998) are also part of the code. Below are some more
technical details and references.

An overview of some of the new capabilities of AMBER 6:

1. LES with PME
AMBER 5 contained the capability for Locally Enhanced Sampling (LES) and
Particle Mesh Ewald (PME), but not both together. These have been
integrated and used in promising ways in prediction of RNA structure
(Simmerling et al, JACS, 120:7149, 1998) and protein structure (Simmerling
et al, JACS,submitted) as well as in free energy calculations of
carbohydrate systems (Simmerling et al, JACS, 120:5771, 1998, and work in
progress). We anticipate this methodology will be very powerful in
structure prediction of complex molecules in solution, since, in contrast to
most other methods, explicit water molecules can be included and thus the
solvation effect considered at the highest level of accuracy.

2. CMC/MD
Chemical Monte Carlo/Molecular Dynamics(CMC/MD) is a new approach to ligand
design, which can consider many molecules at once and is a powerful
complement to more qualitative approaches. In papers published by Pitera
and Kollman (JACS, 120:7557, 1998) and by Eriksson et al. (J. Med. Chem.,
42:868, 1999), it has been shown to be accurate and leads in both cases to a
ligand which was predicted to bind more strongly to the target than the
previous best one considered experimentally.

3. OWFEG free energy grid
The OWFEG(One Window Free Energy Grid) method has been incorporated into the
SANDER module of AMBER 6. OWFEG(Pearlman, J. Med. Chem., 42, 4313, 1999)
allows one to generate an approximate free energy grid about any ligand from
a single molecular dynamics trajectory. OWFEG is based on the PROFEC
approach(Radmer and Kollman, J. Comput-Aided Mol. Des., 12,215, 1998), but
has been generalized to be suitable for use with flexible ligands. As
demonstrated in the OWFEG and PROFEC publications, such grids can provide
very useful guidance in drug design.

4. MM-PBSA (Molecular Mechanics-Poisson Bolzmann/Surface Area)
Case et al. (JACS 120:9401, 1998) have shown that a combination of molecular
dynamics simulations and continuum calculations can be very powerful in
estimating free energy differences even between systems on which one cannot
use free energy perturbation calculations. This methodology is automated in
AMBER 6. This method has proven to be very accurate in calculations of
protein-ligand interactions (Chong et al, PNAS, in press), in
protein-peptide interactions (Massova and Kollman, JACS, 121:8133, 1999),
RNA-protein interactions (Reyes and Kollman, JMB, in press) and protein
folding (Lee et al, Proteins, submitted.)

5. GB/SA
Generalized Born surface area(GB/SA) is a way to put solvation effects
implicitly into calculations of complex systems and recently Tsui and Case
have incorporated this into AMBER 6 for use in minimization and molecular
dynamics calculations. This approach allows one to greatly reduce the
number of atoms in the system by representing solvent implicitly rather than
explicitly. It is estimated that this saves more than an order of magnitude
in simulations of proteins in aqueous solution.

6. Revised PME implementation
AMBER 6 contains a major re-write of the particle-mesh-Ewald (PME)
implementation for molecular dynamics in SANDER. This now accurately This
now supports alternative box shapes(such as the truncated octahedron),
allows polarizable potentials to be used in conjunction with PME and
accurately conserves energy (in the NVE ensemble) over long trajectories.
The user interface for PME calculations has been greatly simplified, so that
in most cases the default parameters should give efficient yet acceptably
accurate results. A variety of accuracy checks and comparisons to "regular"
Ewald summation results are available.

7. NMR refinements
NMR refinements can be carried out with restraints derived from residual
dipolar coupling measurements or with "ambiguous" restraints whose
corresponding NMR spectra are not fully assigned, or for
"multiple-conformer" models generated using the LES algorithm. Routines to
generate restraint input and to interface to NMR data-processing programs
have been considerably expanded.

8. QM/MM Capabilities.
The ROAR 2.0 module contains QM/MM capabilities to carry out QM/MM
minimizations, MD simulations and reaction path following studies.
Semiempirical (PM3, AM1 and MNDO) theory is used for the QM part of
the calculations, while the AMBER force field is the MM part of the
calculation. Minimization can be done using steepest descent,
conjugate gradient or through the use of a limited memory BFGS
approach. The latter approach can also be used in fully classical
minimizations.

9. Multiple Time-Step (MTS) Capabilities
The ROAR module contains the capability to carry out MTS simulations using
the methodology of Berne and co-workers. Conservatively this allows a
doubling of the time-step used, while is special cases much longer
time-steps (e.g., 5fs) can be used. This option is also coupled with the
Nose-Hoover Chain approach to constant T and P simulations and is designed
to work with either standard Ewald or with PME. This option is only set up
to run on condensed phases at this time.

In addition to the capabilities in AMBER 6, a major effort is going on to
broaden the applicability of the force field to more functional groups of
organic molecules, such that one has an accurate representation of both the
conformational and non-bonded interactions of any organic molecule. A paper
in this area has been submitted to J. Comp. Chem. (Junmei Wang and PAK,
submitted) and Wang is further developing the program ANTECHAMBER to enable
efficient handling of many molecules at a time.

AMBER authors

David A. Case
David A. Pearlman
James W. Caldwell
Thomas E. Cheatham, III
Wilson S. Ross
Carlos Simmerling
Tom Darden
Kenneth M. Merz
Robert V. Stanton
Ailan Chen
James J. Vincent
Mike Crowley
Vicke Tsui
Randall Radmer
Yong Duan
Jed Pitera
Irina Massova
George L. Seibel (for contributions to AMBER 3A)
U. Chandra Singh (for contributions to AMBER 2 and 3)
Paul Weiner (for contributions to AMBER 1)
Peter A. Kollman