phmd (c46b2)

Continuous constant pH Molecular Dynamics (PHMD)

Questions and comments should be directed to
-----------------------------------------------------------
Jana Shen (jana.shen@rx.umaryland.edu)
University of Maryland School of Pharmacy


References:
1. M.S. Lee, F. R. Salsbury, Jr., and C.L. Brooks III,
Proteins, 56, 738-752 (2004).

2. J. Khandogin and C.L. Brooks III,
Biophys. J., 89, 141-157 (2005).

3. J. Wallace and J. Shen,
J. Chem. Theory and Comput., 7, 2617-2629 (2011)

4. J. Wallace and J. Shen,
J. Chem. Phys., 137, 184105 (2012).

5. W. Chen, J. Wallace, Z. Yue and J. Shen,
Biophys. J., 105, L15-L17 (2013).

6. Y. Huang, W. Chen, J. Wallace and J. Shen,
J. Chem. Theory and Comput., 12, 5411-5421 (2016).


* Description | Description of the PHMD Commands
* Syntax | Syntax of the PHMD Commands
* Function | Purpose of each of the commands
* Format | Format of the model compound parameter file and how to derive the parameters
* Examples | Example input files for various versions of PHMD

^_
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This module allows one to perform molecular dynamics and simultaneous
titration of specific ionizable residues under specified pH condition.

Titration occurs through the use of lambda variable measuring the
protonation progress of each titrating group. However, only two physical
states exist, namely, lambda = 0 for protonated, and lambda = 1 for
deprotonated states.

The lambda variables, themselves, are functions of theta variables,
through lambda(i) = sin^2[theta(i)]. The thetas can freely propagate without
need for restrictions. When theta = 0, +/- 2n(PI), lambda = 0. When theta = pi
+/- 2n(PI), then lambda = 1. The sin^2 function also provides a natural double
well for quadratic energy functions of lambda.

Analogous to the lambda variables, the x variables measure the tautomer
interconversion progress. The current implementation accounts for two
tautomeric states for either protonated case, such as the carboxylate group, or
deprotonated case, such as the histidine group.

The idea behind titration is that each group has a free energy of
titration when it is an isolated amino acid. in solution In other words, in the
absence of protein, the single group in solvent should spend 50% of the time
protonated and the other 50% of the time deprotonated. To achieve this, a model
energy function has to be derived, which is the potential of mean force of the
model compound titration. In the case of single-site titration (non-tautomer),
the model PMF has a simple quadratic form. In the case of double-site
titration (tautomer), it is a bivariate polynomial (2-d model potential
function), quadratic in both lambda and x variables.

While the same model function can be used for each of the non-termini
groups in the system. We have found that different model functions have to be
used for each possible C- and N-terminus residues. The model compound PMF
parameters are specified in a parameter file, which also serves to select the
desirable titrating groups. Another way to choose or exclude groups from
titration is to use the SELEction keyword in the PHMD command. In the Format
section, the procedure for deriving a model PMF function is explained.

For a double-site titrating group, a new residue type with dummy hydrogens
on both titrating sites has to be defined in the CHARMM topology file. The only
change in the CHARMM parameter file is related to raising the rotation barrier
to the C-O bond to prevent the dummy protons from losing the ability to titrate
once it is rotated to the anti-position (see the example section).

PHMD can be performed in three modes: fully implicit solvent
(using GBSW or GBMV to drive both protonation and conformational sampling);
hybrid solvent (using implicit solvent for protonation sampling and explicit
solvent for conformational sampling); fully explicit solvent (all atom)
(using explicit solvent for both protonation and conformational sampling).

For all-atom PHMD runs, a charge-leveling technique should be used to
maintain the system charge neutrality. In this technique, each titratable site
has a corresponding co-ion or titratable water in the bulk solution.
As the proton titrates, a co-ion or titratable water titrates as well to absorb
the change in the charge.

All-atom PHMD utilizes various electrostatic options. We recommend
either generalized reaction field (GRF) or particle mesh Ewald (PME). The option
applies to both protonation and conformational sampling.

PHMD can also be performed with the GBSW membrane model, preferably
with a cylinder correction for interior dielectrics.

For accelerating convergence in both protonation and conformational sampling,
both temperature and pH based replica exchange protocols have been implemented
in REPDSTR (see additional documentation in repdstr.info). They have also been
implemented in MMTSB toolset.


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[SYNTAX: PHMD commands]

[starting PHMD]

PHMD { PAR <int> WRIte <int> PH <real> NPRInt <int> MASS <real> PHFRQ <int> BETA <real>
BARR <real> BARTAU <real> TEMP <real> MA1 <real> MA2 <real> MA3 <real>
[THETa] [DERIv] } [SELE atom-selection END]
[QCOUple] <int>
[RESI] <int> [RESC] <int>

[test and manipulation commands for PHMD]
used for deriving model PMF parameters

PHTEst { NUM <int> SET <real> }
{ NUM <int> STEP <real> }
{ NUM <int> FORCE <real> POS <real> }


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-----------------------------------------------------------
Parameters of PHMD command
-----------------------------------------------------------

PAR Unit number for PHMD parameter file (input) MUST specify.

WRITE Unit number for PHMD trajectory file (output) MUST specify.

PH Titration pH (default: 1.0)

NPRINT Frequency of writing to PHMD trajectory file (default: 100)

MASS Mass of fictitious theta variable (default: 10)

BARR Quadratic barrier height for each theta variable (default: 2.0)

PHFRQ Frequency of updating theta/lambda variables (default :1)

BETA Friction coefficient (1/ps) for Langevin dynamics of theta/x variables (default: 5.0)
If BETA is zero, dynamics run under Nose' thermostat.

BARTAU Quadratic barrier height for each x variable (default 2.5)

TEMP Thermostat temperature for dynamics of theta/thetax variables (default: 298)

MA1,MA2, Masses in Nose-Hoover thermostat multiplied by MASS.
MA3 (defaults: 3,5,7)

LAM Print lambda values in trajectory file. (default: none)

DERI Print theta and dE/dtheta values (not lambdas) in trajectory file.

SELE Use the SELE keyword to manually specify desirable titratable groups

QCOU Number of titratable groups that couples with coions/titratable water

RESI RESId of the titratable group

RESC RESId of the coion/titratable water

-----------------------------------------------------------
Parameters of PHTE command
-----------------------------------------------------------

NUM Specify titratable group #. Use list generated at beginning
of PHMD output for reference.

SET Set value of theta(NUM)

STEP Increment value of theta(NUM) by STEP

FORCE/POS Place harmonic constraint on theta(NUM) with force constant, FORCE,
at equilibrium position, POS.


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Format of the model PMF parameter file and
How to derive the parameters

The parameter file is a series of entries. Each entry has the format:

1) For single-site titrating groups, such as NTAsp:

(NAME) (EXPERIMENTAL PK_1/2) (A) (B) (BARR)
ATOMTYPE_1 PROT_CHARGE_1 UNPROT_CHARGE_1 [PROT_RAD_1 UNPROT_RAD_1]
ATOMTYPE_2 PROT_CHARGE_2 UNPROT_CHARGE_2 [PROT_RAD_2 UNPROT_RAD_2]
... ... ... ...
ATOMTYPE_N PROT_CHARGE_N UNPROT_CHARGE_N [PROT_RAD_N UNPROT_RAD_N]

NAME : titrating residue name. For C- and N-termini groups, the
name consists of CT (NT) and the terminus residue name,
e.g., CTASP.

A/B : parameters of the PMF function A * ( lambda - B) ^ 2

BARR : barrier for suppressing population of mixed states, or prolonging
residence time for the pure states (default 1.5)

CHARGE : obtained from the CHARMM topology file. Make sure the difference
in the protonated and deprotonated states is 1.

RAD : only needed for the titrating proton: 1.0 for the protonated
form; 0.0 for the deprotonated form

2) for double-site titrating groups, such as ASP, GLU or HIS:

The parameter block for the first tautomer titration has the same look as above:
NAME : One needs to specify parameters for each tautomeric form.
In this case, NAME contains a number, e.g. 1 or 2, which distinguishes
between the first vs. the second tautomer forms.

A/B : coefficients in the quadratic function for the pure tautomeric states.

CHARGE : the dummy atom is assigned with zero charge in both protonated and
deprotonated forms.
Make sure the titrating proton is assigned with VDW radius 1.0 and 0.0.
in the protonated and deprotonated forms, respectively.

The parameter block for the second tautomer titration contains additional
numbers in the first two lines:

(NAME) (EXPERIMENTAL PK_1/2) (A) (B) (BARR) (A10) (B10) (BARTAU)
R1 R2 R3 R4 R5 R6

A10/B10: coefficients in the quadratic function for tautomer interconversion
BARTAU : analog to BARR: barrier for the tautomer interconversion
R1-R6 : parameters for constructing the 2-d model potential function
(bivariate polynomial)

How to derive model parameter values for single-site titration
(using variant of Thermodynamic Integration):

1a) Prepare a coordinate file of the desirable amino acid
capped by ACE and CT3, or un-capped if the terminus
(CT or NT) is to be titrated.

2a) Specify barr = 0, mass=1.E30 and use DERI keyword in the PHMD
input. Use PHTEST command to specify the titrating residue
and its theta value.
Supply a parameter file with pH=exp. pKa and A and B=0.

3a) Run 1ns dynamics at different values of fixed theta between
0 to PI/2. For example, theta = 0.4,0.6,0.8,1.0,1.2, 1.4.
Put corresponding set residue number and

4a) Use trajectory output of derivatives to calculate average
dE/dtheta derivative at each fixed value of theta.

5a) To obtain parameters, A and B, fit the values of dE/dtheta
to the following function, which is dE(model)/dtheta:

2*A*sin(2*theta)*(sin(theta)^2-B)

6a) To verify parameters, run PHMD of the model compound with
parameters plugged into parameter file and check whether the
model system titrates 50% protonated at its experimental pK_1/2.

How to derive model parameter values for double-site titration:

1b) Prepare coordinate file of the model compound with both titrating
sites protonated. A new residue with both sites protonated has to
be defined.

2b) Similar to 2a) except that two "groups" need to be specified
following the command PHTEST. The theta value that follows the
first group corresponds to the titration coordinate lambda while the
theta (or thetax) value that follows the second group corresponds
to the tautomer interconversion coordinate x.

3b) Run 1ns dynamics at different combinations of theta and thetax values
as given in 3a). It is useful to include combinations corresponding to
the pure tautomeric states (thetax=0.0 and PI/2), and the protonated
state (theta=0.0) for carboxyl groups and the deprotonated state
(theta=PI/2) for histidine.

4b) same as in 4a)

5b) Determine A and B as in 5a). For histidine, at theta=PI/2, fit dE/dx to
A10*(x-B10)^2 to obtain A10 and B10.
For carbxyl groups:
Determine R1 R2 and R3 by fitting A(lambda) to R1 lambda^2 + R2 lambda + R3
R4 = 0.5
Determine R5 by fitting A(x) to C1 x^2 + C2 x + R5
Determine R6 by fitting B(x) to C1 x^2 + C2 x + R6


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Usage and topology examples

The examples below illustrate how to use PHMD.
See test/phmd_*.inp for more examples.

-----
NOTES
-----
1) Parameter file must be specified.
2) In implicit or hybrid-solvent mode, it works with GBSW or GBMV
*** note : GBMV does not currently support images,
therefore care should be used when attempting
to use GBMV with hybrid solvent PHMD using
periodic boundary conditions
3) In all-atom mode, it works with PME or GRF

Example 1
*********
! construct a residue with dummy hydrogens for titration

set name = asp

read sequence @name 1
generate @name first ace last ct3 setup
patch aspp2 @name 1
autogen angles dihed
ic para all
ic seed 1 n 1 ca 1 c
ic build
hbuild
ic gene
ic fill
ic edit
dihe 1 cb 1 cg 1 od1 1 hd1 180.0
dihe 1 cb 1 cg 1 od2 1 hd2 180.0
end
coor init sele type hd2 .or. type hd1 end
ic build

(write out psf and pdb files)

Example 2
*********

! Perform a simple PHMD titration simulation on ASP:

set name = Asp
set barr = 2.25
set bartau = 2.5
set ph = 4.0
set temp = 298.0
set phmdpar = phmd-asp.in

(read in asp_h.psf and asp_h.pdb)

(invoke gbsw)

open unit 23 read form name @phmdpar
open unit 25 write form name @{name}.ph-@{ph}.lambda
PHMD PAR 23 WRI 25 PH @ph NPRI 100 -
BARR @barr BARTAU @bartau TEMP @temp

(dynamics)

Example 3
*********

! Same as above except using Langevin dynamics for theta,
using theta update frequency of 10, and running hybrid solvent phmd.

set name = Asp
set barr = 2.25
set bartau = 2.5
set ph = 4.0
set temp = 298.0
set phmdpar = phmd-asp.in

(read in asp_h_solv.psf and asp_h_solv.pdb)

(setup periodic boundary conditions)

(setup images)

(invoke gbsw or gbmv with keyword hybrid) ***» gbsw and gbmv.info

open unit 23 read form name @phmdpar
open unit 25 write form name @{name}.ph-@{ph}.lambda
PHMD PAR 23 WRI 25 PH @ph NPRI 100 BETA 5.0 PHFRQ 10 -
BARR @barr BARTAU @bartau TEMP @temp

(dynamics, where electrostatics option is ewald pmew)

Example 4
*********

! construct a residue with dummy hydrogens for titration and
a titratable water that couples with the residue.

set name = asp

read sequence @name 1
generate @name first ace last ct3 setup
patch aspp2 @name 1
autogen angles dihed
ic para all
ic seed 1 n 1 ca 1 c
ic build
hbuild
ic gene
ic fill
ic edit
dihe 1 cb 1 cg 1 od1 1 hd1 180.0
dihe 1 cb 1 cg 1 od2 1 hd2 180.0
end
coor init sele type hd2 .or. type hd1 end
ic build

read sequ TIPU 1
gene TIPU setup noangle nodihedra
read coor card append
*
3
1 1 TIPU OH2 0.95720 0.00000 0.00000 TIPU 1 0.00000
2 1 TIPU H1 0.00000 0.00000 0.00000 TIPU 1 0.00000
3 1 TIPU H2 1.19719 0.92663 0.00000 TIPU 1 0.00000

coor trans xdir 1 ydir 1 zdir 1 dist 10 sele resn TIPU end
coor orient sele all end

(write out psf and pdb files)

Example 5
*********

! Same as Example 3 except removing gbsw and gbmv with keyword hybrid and indicating
coupled titratable groups and coions.
All-atom phmd is running with the default electrostatics method
pme ***» ewald

set name = Asp
set barr = 2.25
set bartau = 2.5
set ph = 4.0
set temp = 298.0
set phmdpar = phmd-asp.in

(read in asp_h_solv.psf and asp_h_solv.pdb)

(setup periodic boundary conditions)

(setup images)

open unit 23 read form name @phmdpar
open unit 25 write form name @{name}.ph-@{ph}.lambda
PHMD PAR 23 WRI 25 PH @ph NPRI 100 BETA 5.0 PHFRQ 10 -
BARR @barr BARTAU @bartau TEMP @temp -
qcouple 1 -
resi 1 resc 2

(dynamics with PME electrostatics)

Example 6
*********

! Same as Example 4 except using grf method for long-range electrostatics.
Explicit solvent phmd is running with GRF.

set name = Asp
set barr = 2.25
set bartau = 2.5
set ph = 4.0
set temp = 298.0
set phmdpar = phmd-asp.in

(read in asp_h_solv.psf and asp_h_solv.pdb)

(setup periodic boundary conditions)

(setup images)

open unit 23 read form name @phmdpar
open unit 25 write form name @{name}.ph-@{ph}.lambda
PHMD PAR 23 WRI 25 PH @ph NPRI 100 BETA 5.0 PHFRQ 10 -
BARR @barr BARTAU @bartau TEMP @temp
qcouple 1 -
resi 1 resc 2

(dynamics, where electrostatics option is cdie grfe)

Example 7
*********

! Derive model potential function parameters for NtAla

set name = Ntala
set barr = 0.0
set mass = 1.0E30
set ph = 7.5
set temp = 298.0
set phmdpar = phmd-ntala_blank.in
set theta =0.4

(read in ntala_h.psf and ntala_h.pdb)

open unit 23 read form name @phmdpar
open unit 25 write form name @{name}.ph-@{ph}.lambda
phmd par 23 wri 25 ph @ph npri 100 -
barr @barr temp @temp

phtest num 1 set @theta

(dynamics)

Example 8
*********

! Derive model potential function parameters for Asp

set name = Asp
set barr = 0.0
set bartau = 0.0
set mass = 1.0E30
set ph = 4.0
set temp = 298.0
set phmdpar = phmd-asp_blank.in
set theta =0.4
set thetax = 0.4

(read in asp_h.psf and asp_h.pdb)

(invoke gbsw)

open unit 23 read form name @phmdpar
open unit 25 write form name @{name}.ph-@{ph}.lambda
phmd par 23 wri 25 ph @ph npri 100
barr @barr bartau @bartau temp @temp

phtest num 1 set @theta
phtest num 2 set @thetax

(dynamics)

Example 9
*********

! Do some manipulations of the theta variables:

! Incr theta #1 by 0.1
PHTEST NUM 1 STEP 0.1

! Incr theta #5 to 1.5
PHTEST NUM 5 SET 1.5

! Place harmonic restraint on theta #3 with
! force constant 100.0 kcal/mol and
! equilibrium value 0.5
PHTEST NUM 3 FORCE 100.0 POS 0.5

-----------------------------------------------
Additional patches in the CHARMM topology file
-----------------------------------------------
PRES ASPP2 0.00 ! patch for use in PHMD, proton on od1
GROUP ! and od1 via acetic acid, use in a patch statement
! ANGLes DIHEdrals are given
ATOM CB CT2 -0.21 !
ATOM HB1 HA 0.09 ! HB1 OD1-HD1
ATOM HB2 HA 0.09 ! | /
ATOM CG CC 0.75 ! -CB--CG
ATOM OD1 OC -0.55 ! | \
ATOM OD2 OC -0.61 ! HB2 OD2-HD2
ATOM HD1 H 0.0 HD2!
ATOM HD2 H 0.44 HD1!
BOND OD1 HD1
BOND OD2 HD2
DONOR HD1 OD1
DONOR HD2 OD2
IC HD1 OD1 CG OD2 0.0000 0.0000 0.0000 0.0000 0.0000
IC HD2 OD2 CG OD1 0.0000 0.0000 0.0000 0.0000 0.0000

PRES GLUP2 0.00 ! patch for use in PHMD, proton on od1
GROUP ! and od1 via acetic acid, use in a patch statement
! follow with AUTOGEN
ATOM CG CT2 -0.21 !
ATOM HG1 HA 0.09 ! HG1 OE1-HE1
ATOM HG2 HA 0.09 ! | /
ATOM CD CC 0.75 ! -CG--CD
ATOM OE1 OC -0.55 ! | \
ATOM OE2 OC -0.61 ! HG2 OE2-HE2
ATOM HE1 H 0.0 HE2!
ATOM HE2 H 0.44 HE1!
BOND OE1 HE1
BOND OE2 HE2
DONOR HE1 OE1
DONOR HE2 OE2
IC HE1 OE1 CD OE2 0.0000 0.0000 0.0000 0.0000 0.0000
IC HE2 OE2 CD OE1 0.0000 0.0000 0.0000 0.0000 0.0000

PRES CTRP2 0.00 ! patch for protonated CTER, proton on ot2
GROUP ! use in a patch statement, use AUTOGEN, ignore charges
ATOM C CC 0.72 ! OT1-HC1
ATOM OT1 OC -0.55 ! /
ATOM OT2 OC -0.61 ! -C
ATOM HC1 H 0.00 HC2!\
ATOM HC2 H 0.44 HC1! OT2-HC2
BOND OT1 HC1
BOND OT2 HC2
DONOR HC1 OT1
DONOR HC2 OT2
IC HC1 OT1 C OT2 0.0000 0.0000 0.0000 0.0000 0.0000
IC HC2 OT2 C OT1 0.0000 0.0000 0.0000 0.0000 0.0000

RESI TIPP 1.00 ! Hydronium TIP3P - TIPP is resid recognized by pHMD as co-ion
GROUP
ATOM OH2 OZ -0.755 ! From : Sagnella and Voth Biophys. J. (1996) 70:2043-2051
ATOM H1 HZ 0.585 ! Added by Jason A. Wallace
ATOM H2 HZ 0.585
ATOM H3 HZ 0.585
BOND OH2 H1 OH2 H2 OH2 H3 ! real bonds
BOND H1 H2
BOND H2 H3
BOND H3 H1 ! required for shake
ANGLE H1 OH2 H2
ANGLE H2 OH2 H3
ANGLE H3 OH2 H2
ACCEPTOR OH2 H1
ACCEPTOR OH2 H2
ACCEPTOR OH2 H3
DONOR H1 OH2
DONOR H2 OH2
DONOR H3 OH2
PATCHING FIRS NONE LAST NONE

RESI HYDM 1.00 ! Hydronium TIP3P - Copy to be used as primary titration site
GROUP
ATOM OH2 OZ -0.755 ! From : Sagnella and Voth Biophys. J. (1996) 70:2043-2051
ATOM H1 HZ 0.585 ! Added by Jason A. Wallace
ATOM H2 HZ 0.585
ATOM H3 HZ 0.585
BOND OH2 H1 OH2 H2 OH2 H3 ! real bonds
BOND H1 H2
BOND H2 H3
BOND H3 H1 ! required for shake
ANGLE H1 OH2 H2
ANGLE H2 OH2 H3
ANGLE H3 OH2 H2
ACCEPTOR OH2 H1
ACCEPTOR OH2 H2
ACCEPTOR OH2 H3
DONOR H1 OH2
DONOR H2 OH2
DONOR H3 OH2
PATCHING FIRS NONE LAST NONE

RESI TIPU 0.000 ! Protonated hydroxide, recognized by pHMD as co-ion, copy from TIP3
GROUP
ATOM OH2 OXP -0.834
ATOM H1 HXP 0.417
ATOM H2 HXP 0.417
BOND OH2 H1 OH2 H2 H1 H2 ! the last bond is needed for shake
ANGLE H1 OH2 H2 ! required
ACCEPTOR OH2
PATCHING FIRS NONE LAST NONE

RESI HYDX 0.000 ! Protonated hydroxide, to be used as primary titration site, copy from TIP3
GROUP
ATOM OH2 OXP -0.834
ATOM H1 HXP 0.417
ATOM H2 HXP 0.417
BOND OH2 H1 OH2 H2 H1 H2 ! the last bond is needed for shake
ANGLE H1 OH2 H2 ! required
ACCEPTOR OH2
PATCHING FIRS NONE LAST NONE

------------------------------------------------------------------
Additional parameters and modification in the CHARMM parameter file
-------------------------------------------------------------------
! additional parameters for CTRP, ASPP2, TIPP and TIPU
ATOMS
MASS 16 OZ 15.99940 ! hydronium oxygen
MASS 17 HZ 1.00800 ! hydronium hydrogen
MASS 18 OXP 15.99940 ! oxygen of protonated hydroxide
MASS 19 HXP 1.00800 ! hydrogen of protonated hydroxide

BONDS

!V(bond) = Kb(b - b0)**2

!Kb: kcal/mole/A**2
!b0: A

!atom type Kb b0

OC H 545.000 0.9600 ! ALLOW ALC ARO
! copy of EMB 11/21/89 methanol vib fit
HXP HXP 0.0 1.5139 ! Hydroxide - Wei Chen, copy from TIP3
OXP HXP 450.0 0.9572 ! hydroxide - Wei Chen, copy form TIP3
HZ HZ 0.0 1.5630 ! hydronium - J. Wallace
OZ HZ 400.0 0.9517 ! hydronium - J. Wallace

ANGLES

!V(angle) = Ktheta(Theta - Theta0)**2

!V(Urey-Bradley) = Kub(S - S0)**2

!Ktheta: kcal/mole/rad**2
!Theta0: degrees
!Kub: kcal/mole/A**2 (Urey-Bradley)
!S0: A

!atom types Ktheta Theta0 Kub S0


H OC CC 55.000 115.0000 ! ALLOW ALC ARO PEP POL
! copy ! adm jr. 5/02/91, acetic acid pure solvent
HXP OXP HXP 55.0 104.52 ! hydroxide - Wei Chen, copy from TIP3
HZ OZ HZ 50.0 110.40 ! hydronium - J. Wallace

DIHEDRALS

!V(dihedral) = Kchi(1 + cos(n(chi) - delta))

!Kchi: kcal/mole
!n: multiplicity
!delta: degrees

!atom types Kchi n delta

X CD OH1 X 3.0000 2 180.00 ! ALLOW PEP POL ARO ALC MSL
! ! adm jr, 10/17/90, acetic acid C-Oh rotation barrier
! ! Kchi can be modified if needed
X CC OC X 3.0000 2 180.00 ! ALLOW PEP POL ARO ALC MSL
! for CTRP ! Kchi can be modified if needed

IMPROPER

!V(improper) = Kpsi(psi - psi0)**2

!Kpsi: kcal/mole/rad**2
!psi0: degrees
!note that the second column of numbers (0) is ignored

!atom types Kpsi psi0

!OB X X CD 100.0000 0 0.0000 ! ALLOW ALC ARO POL
! adm jr., 10/17/90, acetic acid vibrations
OH1 OB CT2 CD 100.0000 0 0.0000 ! ALLOW ALC ARO POL
! ASPP1

NONBONDED nbxmod 5 atom cdiel shift vatom vdistance vswitch -
cutnb 14.0 ctofnb 12.0 ctonnb 10.0 eps 1.0 e14fac 1.0 wmin 1.5


!V(Lennard-Jones) = Eps,i,j[(Rmin,i,j/ri,j)**12 - 2(Rmin,i,j/ri,j)**6]

!epsilon: kcal/mole, Eps,i,j = sqrt(eps,i * eps,j)
!Rmin/2: A, Rmin,i,j = Rmin/2,i + Rmin/2,j

!atom ignored epsilon Rmin/2 ignored eps,1-4 Rmin/2,1-4


!hydroxide - Wei Chen, copy from TIP3
HXP 0.0 -0.046 0.2245
OXP 0.0 -0.1521 1.7682

!hydronium - J. Wallace
HZ 0.0 -0.046 0.2245
OZ 0.0 -0.1521 1.7682

NBFIX
! Emin Rmin
! (kcal/mol) (A)

OZ OXP -0.1521 4.5 ! adjust to avoid strong electrostatic interaction between hydroxide and hydronium at short distance

END


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Output format

The only output from PHMD is a file that contains lambda values at specified
trajectory time steps. Following is an example output for the titration of ASP
(from phmd_2.inp in test directory):

# ititr 1 2
# ires 1 1
# itauto 3 4
100 0.86 0.25

line 1: gives the numbering for the titrating groups (runs to the total number)
line 2: gives the titrating residue number as in the PDB file
line 3: gives the type of titrating group:
0 - single-site
1 - titration of histidine
2 - tautomer interconversion in histidine
3 - titration of carboxyl groups
4 - tautomer interconversion in carboxyl groups
This information can be used in collecting statistics of protonation
populations.
line 4: column 1: step number; column 2: lambda value; column 3: x value

When PHTEST and DERI commands are used, dU/dtheta is being output. Following is
an example output for ASP (from phmd_1.inp in the test directory) :

# ititr 1 2
# ires 1 1
# itauto 3 4
100 0.4000 5.0330 0.6000 7.5975
200 0.4000 5.1584 0.6000 6.7531

line 3: Two numbers are printed out for each lambda or x trajectories. The first
is the theta or thetax value and the second is dU/dtheta or dU/dthetax,
respectively.