         TINKER: Software Tools for Molecular Design

     Jay W. Ponder, Dept. of Biochemistry and Molecular 
                         Biophysics,
    Washington University School of Medicine, St. Louis, 
                       Missouri 63110

     TINKER is  a complete package for  performing molecular 
mechanics  calculations.  It  is  intended  to  serve  as  a 
platform  for  algorithm development  and  parameterization, 
while still being efficient enough for most production work. 
The  currently  available  potentials  include  MM2(91)  and 
MM3(96), AMBER-95,  AMBER/OPLS, CHARMM22 and our  own TINKER 
potential.   Many  other   literature   potentials  can   be 
implemented via external parameter files; parameter sets for 
ENCAD and MMFF-94 are under development.

     Programs  are   provided  to  perform   many  functions 
including  the  following:   (1)  energy  minimization  over 
Cartesian coordinates, torsional coordinates or rigid bodies 
via conjugate gradient, variable  metric or truncated Newton 
methods, (2) molecular dynamics with periodic boundaries and 
options to control temperature and pressure, (3) normal mode 
vibrational analysis, (4) distance geometry including a new, 
efficient  random   atom-pair  metrization,   (5)  simulated 
annealing with  a choice of cooling  protocols, (6) analysis 
and  breakdown  of  single  point  potential  energies,  (7) 
verification  of  analytical  derivatives  of  the  standard 
potential and/or  user defined functions, (8)  location of a 
transition  state  between  two   minima,  (9)  free  energy 
perturbation  calculations, (10)  fitting of  intermolecular 
potential parameters to  crystal structure and thermodynamic 
data,  and  (11)  diffusion equation  and  Gaussian  density 
annealing  approaches to  global  optimization via  smoothed 
potential energy surfaces.

     Analytical  Cartesian derivatives  through the  Hessian 
and  analytical torsional  derivatives through  the gradient 
are available. Energy  minimization and vibrational analysis 
can   be  performed   in  either   Cartesian  or   torsional 
coordinates. The  user can  define rigid bodies  and compute 
scaled energies between or  within bodies. Atomic multipoles 
through the quadrupole and  explicit dipole polarization, as 
well  as  simplier  electrostatic models,  are  implemented. 
Restraint  potentials  may  be  included  in  all  types  of 
computations or  partial structures can be  frozen in space. 
Both replicative and image boundary conditions are supported 
for all  crystallographic unit cell types  and for truncated 
octahedra.  Interactions within  the desired  cutoff can  be 
located via double loop  searches, classical neighbor lists, 
or the method of lights. Computation of the molecular volume 
and surface area as well  as their derivatives are included. 
Various  macroscopic solvation  models, such  as GB/SA,  are 
implemented. User-defined  functions can be easily  added to 
the standard potentials.

     The heart  of the  TINKER package is  a modular  set of 
callable  subroutines   which  allow  the   manipulation  of 
coordinates   and  evaluation   of   potential  energy   and 
derivatives  in   a  straightforward  fashion.   The  author 
welcomes  development  by other  groups  of  new modules  to 
interface with the TINKER package and is willing to serve as 
a  resource and  distribution  center  for such  development 
efforts.

     The current  package is  written in a  portable Fortran 
dialect that makes use of some common extensions to the ANSI 
FORTRAN-77  standard. Program  control  is  via an  optional 
Keyword Parameter file. Potential  parameters can be altered 
for  all interactions  of  given atom  types/classes or  for 
specific  interactions.  The   coordinate  input  files  are 
compatible  with Cambridge  Scientific Software's  CHEMDRAW-
CHEM3D programs and with the public domain gOpenMol molecule 
viewer.  Auxiliary  programs  are provided  to  interconvert 
Brookhaven Protein Data Bank  Files with the TINKER formats. 
Output can also  be generated in a form  compatible with the 
TRIPOS Sybyl, MSI/BIOSYM InsightII and MSC Xmol programs.

References: 

1. J.  W. Ponder and  F. M.  Richards, An  Efficient Newton-
like Method  for Molecular Mechanics Energy  Minimization of 
Large Molecules, J. Comput. Chem., 8, 1016-1024 (1987).

2. C.  E.  Kundrot,  J.   W.  Ponder  and  F.  M.  Richards, 
Algorithms   for  Calculating   Excluded   Volume  and   Its 
Derivatives  as a  Function  of  Molecular Conformation  and 
Their Use in Energy Minimization, J. Comput. Chem., 12, 402-
409 (1991).

3. M. J.  Dudek and J.  W. Ponder, Accurate Modeling  of the 
Intramolecular Electrostatic Energy  of Proteins, J. Comput. 
Chem.,16, 791-816 (1995).

4. Y.  Kong and  J. W.  Ponder, Reaction  Field Methods  for 
Off-Center Multipoles, J. Chem. Phys., 107, 481-492 (1997).

5. M.  Dudek,  K.  Ramnarayan  and  J.  W.  Ponder,  Protein 
Structure  Prediction   Using  a  Combination   of  Sequence 
Homology   and  global   Energy   Minimization  II.   Energy 
Functions, accepted Sept. '97 for J. Comput. Chem.

Version:       3.5 of October 1997
Language:           FORTRAN 77 with common extensions,
               C translation via f2c available,
               Fortran-90 version under development
Lines of Code:      Approximately 90,000 including comments
