(157c) Using Molecular Dynamics Simulations to Model Entropic Changes upon Peptide Binding

Peptides are promising recognition elements in many biosensing applications. Small in size and easy to produce through both chemical synthesis and biological expression pathways, peptides have many favorable features for use in biosensors. Like all thermodynamic processes, peptide binding is governed by changes in Gibbs Free Energy (ΔG). In turn, ΔG is calculated from changes in Enthalpy (ΔH) and Entropy (ΔS). An issue of current molecular mechanics force fields is the significantly limited manner in which they predict ΔS, consequently giving flawed predictions of ΔG. The motivation of this project is the development of a model that accurately predicts ΔS of peptide binding.

Molecular Dynamics (MD) is a computational method to simulate macromolecular behavior over time. In this study, we focused on small peptides of approximately 10 amino acids in two distinct states: unbound alone in solution as well as bound to a small protein domain in complex. Initial conformations of the peptides were extracted from the RSCB Protein Data Bank (PDB). Unnecessary molecules surrounding the system were removed using Chimera before being prepared using the MD software Visual Molecular Dynamics (VMD) and its QwikMD plugin. 2.5 ns MD simulations of the bound and unbound peptides were performed with explicit solvent molecules, and 100 conformational frames were generated over the course of the simulations. These frames were then clustered to identify the number of structural conformations the peptide experiences in its bound and unbound states. By clustering the repeated conformations being simulated, microstates can be quantified and applied using Boltzmann’s equation, allowing for the calculation of ΔS.

This presentation will discuss our findings from an initial set of 10 diverse peptides, as well as how lessons learned from those peptides are informing a larger study with the overall goal of reliable prediction of ΔS changes from peptide binding.