KBFF20: A Kirkwood-Buff Derived Force Field for Peptides and Proteins

Last Update: June 10, 2021

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, Shin Suh, and Jin Zou.

Contact: pesmith@ksu.edu

Gromacs Files for Peptides and Proteins

The following files provide the full implementation of the KBFF20 model for peptides and proteins in the Gromacs suite (version 2016.4 or later).

KBFF20: kbff20.ff.tar (as of April 2021)

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).

Electrostatic and LJ interactions are evaluated using the PME approach. Note that using PME for the LJ interactions will generate a warning/error for the NT and OT atom types, and for 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.

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.

Documentation

KBFF20 is described in detail in the following publications:

A Kirkwood-Buff Derived Force Field for Peptides and Proteins: Philosophy and Development of KBFF20.

Elizabeth A. Ploetz, Sadish Karunaweera, Nikolaos Bentenitis, Feng Chen, Shu Dai, Moon B. Gee, Yuanfang Jiao, Myungshim Kang, Nilusha L. Kariyawasam, Nawavi Naleem, Samantha Weerasinghe and Paul E. Smith

Journal of Chemical Theory and Computation, 2021, 17 (5), 2964-2990. http://dx.doi.org/10.1021/acs.jctc.1c00075

A Kirkwood-Buff Derived Force Field for Peptides and Proteins: Applications of KBFF20.

Elizabeth A. Ploetz, Sadish Karunaweera and Paul E. Smith

Journal of Chemical Theory and Computation, 2021, 17 (5), 2991-3009. http://dx.doi.org/10.1021/acs.jctc.1c00076

In addition, 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

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	1
Urea	water	2
NaCl	water	3
GdmCl	water	4
Methanol	water	5
Amides	water	6
Thiols and sulfides	methanol	7
Aromatics, Heterocycles	methanol, water	8
Alkali halides	water	9
Alcohols	water	To be published
Amino acids	water	To be published
Alkaline Earth halides	water	10

KB Theory

KB theory is an exact theory of solutions.^11-14 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.¹² 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.¹⁵ 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) 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

(2) 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

(3) 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

(4) 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

(5) 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