It has been established that peptide and protein aggregation lies at the heart of many diseases. Hence, a detailed understanding of exactly when and how peptides or proteins tend to aggregate would be beneficial to a wide range of researchers studying a variety of health related issues. This proposal outlines a program for the systematic study of peptide aggregation using a unique combination of approaches including: currently available experimental thermodynamic data;the theory of preferential interactions as characterized by Kirkwood-Buff (KB) integrals;a simple model for peptide aggregation using preferential interactions between different functional groups in solution;and computer simulation. A theory and model is developed and demonstrated that can decompose and quantify the interactions between different amino acid side chains using existing experimental data on activity coefficients of small peptides, thus enabling predictions of the tendency for aggregation of any small peptide. Computer simulations are proposed to investigate the atomic level details of the aggregation process. A new peptide and protein force field (KBFF) that can reproduce the experimental KB integrals will be completed and used for the simulations.
Aim 1. To quantify and characterize the interactions between functional groups observed in peptides. Analysis of existing experimental data will be performed in aqueous solution to determine preferential interaction (PI) parameters for different amino acid and small peptide systems. A simple model of the Pis will be developed and will then be used to isolate and quantify the Pis between different function groups on those peptides.
Aim 2. To produce an accurate force field specifically designed for the study of preferential interactions in biomolecular systems. The KBFF approach will be extended to include all amino acid side chains.
Aim 3. To understand the role of cosolvents in modifying intermolecular interactions. The addition of cosolvents to a solution of a solute and solvent changes the interactions between the solute molecules. This provides a tool for investigating the strength of intermolecular interactions common in biological systems and how they may be modified. We will focus on the effects of urea and NaCI during our initial studies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (90))
Program Officer
Wehrle, Janna P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Kansas State University
Schools of Arts and Sciences
United States
Zip Code
Ploetz, Elizabeth A; Smith, Paul E (2015) Experimental triplet and quadruplet fluctuation densities and spatial distribution function integrals for liquid mixtures. J Chem Phys 142:094504
Ploetz, Elizabeth A; Karunaweera, Sadish; Smith, Paul E (2015) Experimental triplet and quadruplet fluctuation densities and spatial distribution function integrals for pure liquids. J Chem Phys 142:044502
Ploetz, Elizabeth A; Smith, Paul E (2015) Particle and Energy Pair and Triplet Correlations in Liquids and Liquid Mixtures from Experiment and Simulation. J Phys Chem B 119:7761-77
Pallewela, Gayani N; Smith, Paul E (2015) Preferential Solvation in Binary and Ternary Mixtures. J Phys Chem B 119:15706-17
Ploetz, Elizabeth A; Smith, Paul E (2014) Infinitely dilute partial molar properties of proteins from computer simulation. J Phys Chem B 118:12844-54
Ploetz, Elizabeth A; Smith, Paul E (2013) Local Fluctuations in Solution: Theory and Applications. Adv Chem Phys 153:311-372
Karunaweera, Sadish; Gee, Moon Bae; Weerasinghe, Samantha et al. (2012) Theory and Simulation of Multicomponent Osmotic Systems. J Chem Theory Comput 8:3493-3503
Zhang, Ting; Ploetz, Elizabeth A; Nagy, Maria et al. (2012) Flexible connection of the N-terminal domain in ClpB modulates substrate binding and the aggregate reactivation efficiency. Proteins 80:2758-68
Zolkiewski, Michal; Zhang, Ting; Nagy, Maria (2012) Aggregate reactivation mediated by the Hsp100 chaperones. Arch Biochem Biophys 520:1-6
Gee, Moon Bae; Cox, Nicholas R; Jiao, Yuanfang et al. (2011) A Kirkwood-Buff Derived Force Field for Aqueous Alkali Halides. J Chem Theory Comput 7:1369-1380

Showing the most recent 10 out of 26 publications