###########################################################################
# Application of the BOLAS free-energy algorithm to gererate free energy  #
# profiles in biomolecular systems. The utility can be applied to either  #
# (a) locate transition state regions using 				  #
#     transition path sampling (TPS), or  				  #
# (b) compute potential of mean force using BOLAS.                         #
#      									  #
# Authors: Ravi Radhakrishnan, Tamar Schlick				  #
# Address: Department of Chemistry and Courant Institute of Mathematical  #
#          Sciences, New York University, 31 Washington Place, Main 1001  #
#          New York, NY 10003						  #
# Contact: rr38@cornell.edu, schlick@nyu.edu				  #
# Primary references							  #
# BOLAS: 								  #
# R.Radhakrishnan, T.Schlick, J. Chem. Phys., in press 121(4), (2004)     #
# Transition Path Sampling:						  #
# C.Dellago, P.G.Bolhuis, and P.L.Geissler, Adv. Chem. Phys 123, 1 (2002) #
###########################################################################

This directory contains files that illustrate successful runs of
transition path sampling and BOLAS to a sugar repuckering transition
in deoxyadenosine molecule. The executables provided here are for a
SGI ORIGIN R10000+ workstation. The directory in compressed format
(*.tar.gz) can be downloaded from:

http://www.seas.upenn.edu/~biophys/dissemination/bolas_distribution.tar.gz

The description of files are as follows.

bolas.pl

A PERL script that performs the transition path sampling and bolas
sampling runs. Section 1 of the script is specific to each run and
must be updated by the user to customize the runs. In the current
example, variables in section 1 are set to perform the sugar repucker
transition in deoxyadenosine. The script runs CHARMM dynamics
jobs. CHARMM input files are prepared by the script and CHARMM jobs
are dispatched to a queuing system. The script then waits around (by
periodically checking if the CHARMM jobs are complete) and then
analyzes the CHARMM results to figure out whether to accept or reject
the new set of trajectories. The script then goes on to submit new
CHARMM jobs.

tpsbarefile
tpsbarefile2

These "bare" files look like charmm input files and are templates that
the PERL script uses to generate a charmm input file. The PERL script
generates the initial part of the input file (by setting the variables
in the commented lines in the "barefile") and concatenates it to the
"bare" files to produce a complete charmm input file. The barefile2
performs analysis on the trajectories. In the current example, it
computes the pucker angle as a time series for the generated dynamics
trajectories. The path to the "barefiles" are set in section 1 of the
PERL script.

top_all27_prot_na.inp
par_all27_prot_na.inp

These are not included with this distribution and have to be obtained
from the CHARMM developers. See http://charmm.org for more details.

CHARMM topology and parameter files that come along with the CHARMM
distribution. (See CHARMM documentation.)

nusa_equil.crd

CHARMM coordinate file that contains the coordinates of the
deoxyadenosine molecule. This file is read in the charmm input files
provides a starting configuration for the dynamics trajectories.

Mcharmm_c28a3
charmm

These are not included with this distribution and have to be obtained
from the CHARMM developers. See http://charmm.org for more details.

Charmm executables (mpi and single version). The input files may have
to be updated slightly to make them consistent with more recent
versions of CHARMM. See CHARMM documentation to compile and produce
these executables. The executables are run from within the PERL script
several times. The path to the executables are set in section 1 of the
PERL script.

random.f
random

Fortran77 source and executable files for random number generator. The
"ran3" subroutine from numerical recipies in fortran is employed
here. The executable is run from within the PERL script several
times. The path to this executable is set in section 1 of the PERL
script.

tps_bol_ck.f
tps_bol_ck
bead_bol_ck.f
bead_bol_ck

Fortran 90 source and executable files for post analysis of CHARMM
runs. The executables are run from within the PERL script several
times. The path to the executables are set in section 1 of the PERL
script. They produce time series of conformational variables that
decide whether a particular trajectory visits a specified region of
phase space. These executables also require a file named "shckfls" to
be present (see runfiles/ below for more information). The output of
"tps_bol_ck" is "*_out" and that of "bead_bol_ck" is "*2_bdd" (see
tpsrun/ and bolasrun/ below). For example, the unix command "echo 1 |
tps_bol_ck" produces "*1_out" file. This command is run from within
the PERL script; the unix command "echo 2 | tps_bol_ck" produces
"*2_out" file; the unix command "bead_bol_ck" produces "*2_bdd".

tpsrun/
bolasrun/

These directories contain charmm output including dynamics files and are
therefore not included with the distribution because of their large
size. They can be downloaded in compressed format (*.tar.gz) from:

http://monod.biomath.nyu.edu/~rradhak/bolas/tpsrun.tar.gz
http://monod.biomath.nyu.edu/~rradhak/bolas/bolasrun.tar.gz

Directories that contain outputs of successful transition path
sampling and BOLAS runs for the sugar repuckering transition in
deoxyadenosine molecule. For example, the sh_gn006_xxxpr* files in
"tpsrun" are associated with the sixth generation of harvested
trajectories during the transition path sampling run. The MARKOV chain
of accepted generations are listed in the "sampling_tps" and
"sampling_bolas" files and are used to compute Monte Carlo averages of
conformational variables, autocorrelation functions etc. The
"race_history.log_*" files are log files of the runs and are used to
verify consistency and debugging of the PERL script.

runfiles/

The files in this directory are generated and employed by the PERL
script: "current_file" stores the current accepted generation; "nproc"
stores an integer value that sets the number of processors in CHARMM
runs; nproc can be updated anytime. The PERL script periodically
(every generation) reads nproc to reset the number of processors. To
terminate a run type "cp end generation_status" at command line in the
executable directory. This terminates the sampling run after
completing the current generation. The log file contains a line
"DECIMATION INVOKED" and the PERL script terminates. The file "shckfls"
contains names of the current generation of trajectories and is needed
to execute the "tps_bol_ck" and "bead_bol_ck" to produce the "_out" and
"_bdd" files associated with that generation.

miscellaneous/

pert.inp: CHARMM input file that illustrates the velocity perturbation
in a shooting move.

traj_puc.f, traj_puc: Fortran90 source and executable for analysis of
runs. The executable needs the sampling file and the harvested
trajectories of the sampling run and is executed using the unix
command "traj_puc". The output is a file named "trajpuc", which contains
a timeseries of pucker and phase angle in the accepted
trajectories. The unix command "xmgr trajpuc" enables the
visualization of the time series if the plotting program "XMGR" is
installed.

corr_puc.f, corr_puc: Fortran90 source and executable for analysis of
runs. The executable needs the "sampling" file and the harvested
trajectories of the sampling run, and is executed using the unix
command "corr_puc". The output is a file named "corrpuc", which contains
autocorrelation of pucker angle calculated from the accepted trajectories.

references/

Application of transition path sampling and bolas to polymerase beta:

Ravi Radhakrishnan and Tamar Schlick, Orchestration of cooperative
events in DNA synthesis and repair mechanism unraveled by transition
path sampling of DNA polymerase beta's closing,
Proc. Nat. Acad. Sci. USA, 101(16), 5970-5975 (2004)

tps_polbeta.pdf

Supplementary Material

tps_polbeta_sup1.pdf
tps_polbeta_sup2.pdf
tps_polbeta_sup3.pdf
tps_polbeta_sup4.html

Formulation and applications of bolas:

Ravi Radhakrishnan and Tamar Schlick, Biomolecular free energy
profiles by a shooting umbrella sampling protocol ("BOLAS"),
J. Chem. Phys., 121(4), in press. (2004)

bolas_dA.pdf