The Kirkwood-Buff Derived Force Field (KBFF) Homepage

 

Last Update: January 9, 2018

 

Developers

Paul E. Smith, Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA

Samantha Weerasinghe, Department of Chemistry, University of Colombo, Colombo 00300, Sri Lanka

We would also like to acknowledge valuable contributions from: Nikolaos Bentenitis, Feng Chen, Rajappa Chitra, Shu Dai, Moon Bae Gee, Yuanfang Jiao, Myungshim Kang, Nilusha Kariyawasam, Sadish Karunaweera, Davide Mercadante, Nawavi Naleem, Gayani Pallewela, Elizabeth A. Ploetz, and Jin Zou.

Contact: pesmith@ksu.edu

 

Gromacs Files for Peptides and Proteins

The following files provide the full implementation of the KBFF models for peptides and proteins in the Gromacs suite (version 2016.4).

            KBFF for Proteins Version 3 – tar file (kbffpv3.ff.tar) – January 2018

KBFF for Proteins Version 2 – tar file (kbffpv2.ff.tar) – June 2015

KBFF for Proteins Version 1 – tar file (kbffpv1.ff.tar) – March 2013 – now obsolete

Unfortunately, we do not have parameters for cofactors (heme, transition metals), nor do we have the KBFF files setup for any other simulation codes. The tar file should be extracted in the main top directory (usually /usr/local/gromacs/share/gromacs/top). There are a few files in the top directory that then need to be modified slightly before use (as described in the README file). The only difference between versions 1 and 2 involves the ϕ/ψ potentials. Version 2 uses a CMAP approach for gly and non-gly residues and has been more thoroughly tested. This is intended to fix a problem in version 1 where beta type secondary structures are observed to be slightly too unstable in long (΅s) simulations. Version 3 represents our most recent attempt to reproduce folding equilibria for small alpha and beta forming peptides. This includes further refinement of the ϕ/ψ and a refitting of the χ dihedrals to the distributions observed in recent database analyses.1,2 Version 1 was only available for internal use. Version 2 was released with limited availability. Version 3 should be regarded as the first official full release (manuscript to follow).

 

Motivation

Common force fields for the simulation of biological systems are known to perform poorly under certain circumstances. For instance, when used in drug design studies it is typically observed that structural predictions are very good, but the scoring or ranking is much more problematic. Simulations of protein denaturation have also indicated high melting temperatures compared to experiment, and an over collapse of the denatured state ensemble. The main aim here is to provide an efficient, non-polarizable, united atom classical force field for the simulation of peptides and proteins that provides an improved description of the interactions in these systems. The force field parameters (mainly the effective condensed phase partial atomic charges) are obtained by attempting to reproduce the experimental Kirkwood-Buff (KB) integrals as a function of composition for a variety of binary solute and solvent (mainly water) systems. The solutes were chosen to represent the typical functional groups found in amino acids. We consider this an alternative to the traditional approach for biological force fields. Whether this leads to significantly improved results has yet to be fully determined. However, initial studies appear promising.3-6

 

Documentation

The full paper describing the force field is still under preparation. However, several mini-reviews have appeared:

 

            Accurate Force Fields for Molecular Simulation.

            Elizabeth A. Ploetz, Samantha Weerasinghe, Myungshim Kang and Paul E. Smith.

In P. E. Smith, E. Matteoli and J. P. O’Connell, editors, Fluctuation Theory of Solutions: Applications in Chemistry, Chemical Engineering, and Biophysics, pages 117-132, CRC Press, Boca Raton, 2013.

 

Developing Force Fields from the Microscopic Structure of Solutions: The Kirkwood-Buff Approach.

Samantha Weerasinghe, Moon Bae Gee, Myungshim Kang, Nikolaos Bentenitis, and Paul E. Smith.

In M. Feig, editor, Modeling Solvent Environments, pages 55-76, Wiley-VCH, Weinheim, 2010.

 

            Developing Force Fields from the Microscopic Structure of Solutions.

            Elizabeth A. Ploetz, Nikolaos Bentenitis, and Paul E. Smith.

            Fluid Phase Equilibria, 2010, 290 (1-2), 43-47.

         http://dx.doi.org/10.1016/j.fluid.2009.11.023

           

In addition, a series of publications have appeared describing the parameterization procedure for specific small solutes representative of amino acid sidechains and common cosolvents.

 

Solute

Solvent

Reference

Acetone

water

7

Urea

water

8

NaCl

water

9

GdmCl

water

10

Methanol

water

11

Amides

water

12

Thiols and sulfides

methanol

13

Aromatics, Heterocycles

methanol, water

14

Alkali halides

water

15

Alcohols

water

To be published

Amino acids

water

To be published

Alkaline Earth halides

water

16

 

 

KBFF Equations

The KBFF potential energy expressions are quite simple. There is no explicit polarization and united atom non-polar groups are used when appropriate (aromatic ring hydrogens are included).  The total potential energy is given by the following terms:

where all the symbols have their usual meaning (see the Gromacs manual, for instance). The KBFF models have been developed in combination with the SPC/E water model. Hence, we consider the models to implicitly include polarization corrections.17 All bonds are constrained to be rigid using Lincs for non-water bonds and SETTLE for water bonds. Bond lengths, together with the angle and improper terms, are taken directly (with permission) from the Gromos 53a6 force field provided with Gromacs. Side chain torsional potentials involving hydrogens are based on literature QM calculations,18 and the observed preferences for χ dihedrals in the PDB.19 The ϕ/ψ potentials were developed independently and implemented using the CMAP option in Gromacs. All nonbonded interactions were developed by the Authors, with the exception of the hydrocarbon parameters which are taken from the literature.20 Geometric combination rules are used for both sigma and epsilon parameters - although the combination rules are broken for alkali and alkaline earth cation interactions with water. The 1-4 LJ and Coulomb interactions are scaled by 0.1 and 0.5, respectively. Electrostatic and LJ interactions are evaluated using the PME approach. Note that using PME for the LJ interactions will generate an warning/error for the alkali and alkaline earth metals, where the sigma combination rule is broken, resulting in an incorrect description of the LJ interaction in k-space when using a grid based approach. We consider this to have a negligible effect on the simulation results for normal systems. A sample Gromacs mdp file is included listing the standard settings associated with the KBFF models.

           

KB Theory

KB theory is an exact theory of solutions.21-24 KB theory provides a link between integrals over the molecular distribution functions between each species present in solution, and the thermodynamic behavior of the solution.22 The resulting integrals (KBIs) can be obtained from an analysis of the experimental activities, partial molar volumes, and isothermal compressibility as a function of composition.25 The integrals can be used to quantify the relative distribution of each species around each other species. We have used the composition dependent experimental KBIs for binary solutions as target data for our force fields in an attempt to ensure an appropriate balance between the solute-solute, solute-solvent, and solvent-solvent distributions. In general, we find this can be achieved without sacrificing agreement with experiment for other thermodynamic and dynamic properties of the mixtures.

 

Other Links

Small molecule Gromacs itp files – coming soon

Final PDB files for simulated systems – coming soon

Full publication list of Paul E. Smith

 

Funding

We are grateful to the following agencies for financial support over the years - NSF, NIH, ACS PRF, NSF-GK12 and KSU.

 

Literature

(1)       Fitzkee, N. C.; Fleming, P. J.; Rose, G. D. The Protein Coil Library: A Structural Database of Nonhelix, Nonstrand Fragments Derived from the Pdb. Proteins-Structure Function and Bioinformatics 2005, 58, 852-854.

http://dx.doi.org/10.1002/prot.20394

(2)       Shapovalov, M. V.; Dunbrack, R. L. A Smoothed Backbone-Dependent Rotamer Library for Proteins Derived from Adaptive Kernel Density Estimates and Regressions. Structure 2011, 19, 844-858.

http://dx.doi.org/10.1016/j.str.2011.03.019

(3)       Weerasinghe, S.; Gee, M. B.; Kang, M.; Bentenitis, N.; Smith, P. E. Developing Force Fields from the Microscopic Structure of Solutions. In Modeling Solvent Environments, Feig, M., Ed. Wiley-VCH: Weinheim, 2010.

(4)       Mercadante, D.; Milles, S.; Fuertes, G.; Svergun, D. I.; Lemke, E. A.; Grater, F. Kirkwood-Buff Approach Rescues over-Collapse of a Disordered Protein in Canonical Protein Force Fields. Journal of Physical Chemistry B 2015, 119, 7975–7984.

http://dx.doi.org/10.1021/acs.jpcb.5b03440

(5)       Goh, G. B.; Eike, D. M.; Murch, B. P.; Brooks III, C. L. Accurate Modeling of Ionic Surfactants at High Concentration. Journal of Physical Chemistry B 2015, 119, 6217-6224.

http://dx.doi.org/10.1021/acs.jpcb.5b01765

(6)       Ploetz, E. A.; Weerasinghe, S.; Kang, M.; Smith, P. E. Accurate Force Fields for Molecular Simulation. In Fluctuation Theory of Solutions: Applications in Chemistry, Chemical Engineering and Biophysics Smith, P. E.; Matteoli, E.; O' Connell, J. P., Eds. CRC Press: Boca Raton, 2013; pp 117-132.

(7)       Weerasinghe, S.; Smith, P. E. Kirkwood-Buff Derived Force Field for Mixtures of Acetone and Water. Journal of Chemical Physics 2003, 118, 10663-10670.

http://dx.doi.org/10.1063/1.1574773

(8)       Weerasinghe, S.; Smith, P. E. A Kirkwood-Buff Derived Force Field for Mixtures of Urea and Water. Journal of Physical Chemistry B 2003, 107, 3891-3898.

http://dx.doi.org/10.1021/Jp022049s

(9)       Weerasinghe, S.; Smith, P. E. A Kirkwood-Buff Derived Force Field for Sodium Chloride in Water. Journal of Chemical Physics 2003, 119, 11342-11349.

http://dx.doi.org/10.1063/1.1622372

(10)     Weerasinghe, S.; Smith, P. E. A Kirkwood-Buff Derived Force Field for the Simulation of Aqueous Guanidinium Chloride Solutions. Journal of Chemical Physics 2004, 121, 2180-2186.

http://dx.doi.org/10.1063/1.1768938

(11)     Weerasinghe, S.; Smith, P. E. A Kirkwood-Buff Derived Force Field for Methanol and Aqueous Methanol Solutions. Journal of Physical Chemistry B 2005, 109, 15080-15086.

http://dx.doi.org/10.1021/Jp051773i

(12)     Kang, M.; Smith, P. E. A Kirkwood-Buff Derived Force Field for Amides. Journal of Computational Chemistry 2006, 27, 1477-1485.

http://dx.doi.org/10.1002/Jcc.20441

(13)     Bentenitis, N.; Cox, N. R.; Smith, P. E. A Kirkwood-Buff Derived Force Field for Thiols, Sulfides, and Disulfides. Journal of Physical Chemistry B 2009, 113, 12306-12315.

http://dx.doi.org/10.1021/Jp904806f

(14)     Ploetz, E. A.; Smith, P. E. A Kirkwood-Buff Force Field for the Aromatic Amino Acids. Physical Chemistry Chemical Physics 2011, 13, 18154-18167.

http://dx.doi.org/10.1039/C1cp21883b

(15)     Gee, M. B.; Cox, N. R.; Jiao, Y. F.; Bentenitis, N.; Weerasinghe, S.; Smith, P. E. A Kirkwood-Buff Derived Force Field for Aqueous Alkali Halides. Journal of Chemical Theory and Computation 2011, 7, 1369-1380.

http://dx.doi.org/10.1021/Ct100517z

(16)     Naleem, N.; Bentenitis, N.; Smith, P. E. A Kirkwood-Buff Derived Force Field for Alkaline Earth Halide Salts Journal of Chemical Physics 2018, in press.

(17)     Berendsen, H. J. C.; Grigera, J. R.; Straatsma, T. P. The Missing Term in Effective Pair Potentials. Journal of Physical Chemistry 1987, 91, 6269-6271.

http://dx.doi.org/10.1021/j100308a038

(18)     Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. Journal of the American Chemical Society 1996, 118, 11225-11236.

http://dx.doi.org/10.1021/Ja9621760

(19)     Lovell, S. C.; Word, J. M.; Richardson, J. S.; Richardson, D. C. The Penultimate Rotamer Library. Proteins-Structure Function and Genetics 2000, 40, 389-408.

http://dx.doi.org/10.1002/1097-0134(20000815)40:3<389::Aid-Prot50>3.0.Co;2-2

(20)     Schuler, L. D.; Daura, X.; van Gunsteren, W. F. An Improved Gromos96 Force Field for Aliphatic Hydrocarbons in the Condensed Phase. Journal of Computational Chemistry 2001, 22, 1205-1218.

http://dx.doi.org/10.1002/Jcc.1078

(21)     Kirkwood, J. G.; Buff, F. P. The Statistical Mechanical Theory of Solutions .1. Journal of Chemical Physics 1951, 19, 774-777.

http://dx.doi.org/10.1063/1.1748352

(22)     Ben-Naim, A. Molecular Theory of Solutions. Oxford University Press: New York, 2006.

(23)     Ploetz, E. A.; Smith, P. E. Local Fluctuations in Solution: Theory and Applications. Advances in Chemical Physics 2013, 153, 311-372.

http://dx.doi.org/10.1002/9781118571767.ch4

(24)     Ploetz, E. A.; Smith, P. E. Particle and Energy Pair and Triplet Correlations in Liquids and Liquid Mixtures from Experiment and Simulation. Journal of Physical Chemistry B 2015, 119, 7761-7777.

http://dx.doi.org/10.1021/acs.jpcb.5b00741

(25)     Ben-Naim, A. Inversion of Kirkwood-Buff Theory of Solutions - Application to Water-Ethanol System. Journal of Chemical Physics 1977, 67, 4884-4890.

http://dx.doi.org/10.1063/1.434669