Free Energy Calculation of Melittin in Lipid Bilayer Using Molecular Dynamics Simulation

1.Abstract

Melittin is the most widely studied antimicrobial peptide and has gained interest because of its potential in therapeutic use.
Based on the previous study, it is believed that the antimicrobial action of melittin involves forming a toroidal pore in the bacterial membrane
that eventually leads to cell death. To gain the insight how this process occurs, we perform molecular dynamics simulation using different orientations
of melittin to the bilayer surface as the initial conformation. We then calculate the free energy to asses the most stable structure of this peptide inside the lipid bilayer. To do so, umbrella sampling method is conducted to determine the coordinate for which the free energy curve is calculated. In addition, we use a mixing type of lipid bilayer POPE and POPC to explore its effect towards the antimicrobial interaction with the membrane

2.Keywords
melittin, lipid bilayer, free energy, MD simulation
3.Objective

1. Investigate the interaction of antimicrobial peptide in different orientation towards surface state or transmembrane state of the POPC:POPE lipid bilayer using molecular dynamics simulation
2. Analyze the stable structure of melittin in membrane system through the calculation of its free energy

4.Methodology

In this study, molecular dynamics (MD) simulation is carried out by using GROMACS package: version 4.6.5. Melittin and POPC:POPE lipid bilayer were described with the GROMOS96 43a1 and Berger lipid force fields. SPC water model was adopted to describe water molecule.
Generally, MD simulation can be divided into three processes:
- Minimization is the process of finding an arrangement of the atoms which represent a local or global energy minimum. This process is performed to avoid too close contact, overlap or might even occupy nearly the same space, which leading to high repulsive energy. If MD simulation straightly perform without this process, the system would be unstable because the high energy. During minimization, the system experiences the relaxation of the binding parameter (bond lengths, angles, and torsions). The lower the energy of the system, the more stable it is, and the fewer unfavorable interaction there exist.
- Equilibration
In this process, the melittin is in position restraint to let all water molecules equilibrate around the peptide in order to fill holes, crevices and so on. Also, these water molecules have to re-orient around the lipid headgroup. Moreover, the lipid molecules have to orient themselves around the peptide. During equilibration, the energy components such as pressure, temperature, density, etc, will be calculated to assess how equilibrium the system is. The simulation time of this process is strongly depend on the size of the system.
- Production Run
After the system is well-equilibrated, the position restraint can be release and the process can be extent to achieve a desired conditions.

5.Team
6.Computation plan (required processor core hours, data storage, software, etc)

8 cores
200 GB
MD Simulation Package: GROMACS 4.6.5
Energy Representation method program (ERmod 0.3 beta 1)

7.Source of funding
8.Target/outputs
APS International Proceeding
9.Date of usage
01/07/2015 - 31/10/2015
10.Gpu usage
use gpu
11.Supporting files
prop_1435720135.pdf
12.Created at
01/07/2015
13.Approval status
approved