(6cl) Molecular Modeling of Anti-Microbial Peptides at a Water-Lipid Bilayer Interface

In the last 20 years, interest in peptide folding mechanisms at water-membrane interfaces and peptide-membrane interactions has increased in diverse biological fields. A example is the interaction of anti-microbial peptides (AMP) against bacterial membrane. Research studies show future potential of AMPs as an applicable antibiotic drug. Although experimental studies have explored the details of AMP-membrane interactions by suggesting significant roles of the structure of peptide, the kind of amino acid sequences, and the structure of membrane, there is still much uncertainty in the exact mechanism of cell death by AMPs and the relationship between the structure of AMPs and its antibacterial functionality. Molecular modeling provides atomistic details and 3D structure of peptide-membrane interaction that contributes to investigation of this mechanism and also can help to find which biophysical parameters and AMPs characteristics can affect the performance of AMPs. Prior computational studies demonstrate the crucial effect of hydrophobicity, charge and the helical structure of peptides, and important role of aromatic amino acids such as Tryptophan (TRP) and Tyrosine (TYR) during interactions with membranes.

In my research under supervision of Professor Michael Greenfield, as a general aspect, I attempt to understand how changes in amino acid residues have an effect on peptide folding and peptide-membrane interactions. To that end, I am focusing on the structures of novel hybrid AMPs LM7-1 and LM7-2 at water-membrane interface. These peptides were designed previously using combinations of naturally occurring AMPs, and they differ in sequence only at the 15th residue. Prior experimental results indicate different performance of these two AMPs against diverse bacteria. One of the potential explanation for this issue can be the different folded structure of these AMPs at a water-membrane interface. Molecular dynamics (MD) simulation is used as an appropriate tool to investigate the details of AMP and membrane structure exactly in the moment of interaction. The hydrophobicity distribution on the folded structure of peptide, the deviation of peptide from helical structure at the moment of binding with membrane, and the pore formation structure on the membrane are all key points that can be analyzed using the results of MD simulation. However, all of these kinds of studies depend on the accuracy of the simulation.

The accuracy of biomolecular modeling results is based in part on force field (FF) parameters. Several simulation studies have proved that applying different FFs leads to various peptide folded structures and consequently results in different functionalities of peptide. The results from the first steps of these simulations on the basis of Charmm36 FF show that the structures of aromatic rings (TRP and TYR) have deviations from planarity. These aromatic amino acids have an effective role in the peptide-membrane interaction. Hence, I investigated the geometry and inherent nonplanar vibrations of these aromatic rings in more detail. I applied all-atom Normal Mode Analysis (NMA) on the results of the MD simulation to calculate the inherent vibrations of atoms. On the basis of this analysis, some deficiencies in calculated nonplanar mode frequencies from Raman spectroscopy and the results of quantum calculation have been observed. We found that Charmm36 has not considered improper torsion for atoms in the ring of TRP and TYR. Including improper torsion in simulation brings atoms in the ring of TRP and TYR to a planar structure. However, the nonplanar vibrational modes shifted to higher frequencies compared to Raman Spectra and to results of quantum calculation. Beside the improper torsion, torsion angle that include atoms in the ring have a direct effect on nonplanar vibrations. By including the improper torsion with specific force constants and applying a specific set of amended torsion angles parameters, we could fix the pattern and frequencies of nonplanar modes that can match with Raman spectra and the resutls of quantum calculations. In summary, we modified charmm36 FF to provide proper dynamics and structures for atoms of TRP and TYR.

Investigating the journey of peptide from coil structure in solution to folded structure at a water-membrane interface can help us to find how the one different residue in the sequence of LM7-1 and LM7-2 leads the peptide to a different path of the folding process. MD simulation can explore the conformational space for a peptide folding process. Since large-scale motions in peptide are a consequence of small-amplitude fluctuations, it is also essential to investigate the individual atomic fluctuations over MD simulation. NMA is applied on the configuration results of MD simulations of peptide in solution or at water-membrane interface. This calculation provides the vibrations in a peptide and also provides ta surface energy map that shows which specific vibrational modes lead a peptide to be folded or unfolded. Comparing analysis for both LM7-1 and LM7-2 can help us understand how one difference in the peptide sequence affects their performance against a bacterial membrane. The outcome of the computational studies will contribute to explaining atomistic detail in the process of peptide folding at water-membrane interfaces, and also will provides a proper perspective in understanding biophysical characteristics of peptide-membrane interactions.

Future Research Interests:

I would like to expand my research to study the structure and the interaction of biomolecules at interfaces by applying molecular modeling. Besides peptide or protein folding at a water-membrane interface, which is my current research and I explained it above, I am interested in nanoparticle-membrane interactions, especially nowadays that the implementation of nanoparticles (NPs) in drug delivery is increasing. Investigating the effect of physical parameters such as hydrophobicity and charge distribution provides insight to the design of biocompatible NP structure for pharmaceutical applications. In addition, the interaction of protein with NPs and understanding the formation mechanism of protein corona in atomistic detail is another significant phenomena from the perspective of NPs toxicity.

Teaching Interests:

Beside my research career, I have extensive teaching experience of about 12 years that shows my intensive interest in teaching. I believe teaching helps me to achieve the deeper level of understanding. I started teaching at high school and institutes when I was an undergraduate student. As a PhD student, I continued teaching as a teaching assistant (TA) at University of Rhode Island (URI) for 4 years. During these four years, I have been chosen to be a TA for diverse courses. Even as a Ph.D student, I had the opportunity to be the sole instructor of “Chemical Engineering Thermodynamics 1” course (CHE313-spring 2017) at URI.

My previous experiences in teaching:

1- Instructor of “ Chemical Engineering Thermodynamics 1” at URI – Spring 2017

2- TA for Senior Chemical Engineering Lab – 9 semesters at URI

3- TA for courses: Chemical Kinetics and Reactor Design, Thermodynamics 1 and 2, Engineering Materials, Chemical Process Calculations.

4- Teacher in Iran of Chemistry and Geometry, Analytical Geometry, Linear algebra for 8 years at high school and university entrance exam preparation institutes.

In the future, I am most interested in teaching:

1- Applied mathematics in chemical engineering

2- Molecular modeling

3- Thermodynamics

4- Mass transfer

5- Heat transfer

6- Fluid Mechanic

7- Unit Operations