(7if) Molecular Modeling of Anti-Microbial Peptides at Water-Membrane 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. An example is the interaction of anti-microbial peptides (AMP) against the bacterial membranes. Since the resistance of bacteria against conventional antibiotics is increasing, the interest in developing of new antibiotics with high level of performance has arisen. Research studies show future potential of AMPs as an applicable antibiotic drug based on two main reasons: The unique mechanism of actions and rapid killing of bacteria. AMPs mechanism of action involves its interaction with the lipid membrane of bacteria. The experimental studies suggested that the structure of peptide, the kind of amino acid sequences and the structure of membrane play the most significant roles in this mechanism. Hence, the study of 3D structure of peptide and membrane is the key to understand this mechanism. In spite of experiments that explored the details of peptide-membrane interactions, 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. Spectroscopic techniques especially NMR help toward a better understanding of the structure of peptide and membrane; however, these methods just provide a different points of view of peptide activities and cannot completely determine the AMPs-membrane interaction. Molecular modeling provides atomistic details of peptide-membrane interaction which 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 during interactions with membranes. These studies also point out the important role of aromatic amino acids such as Tryptophan (TRP) and Tyrosine (TYR) in peptide-membrane interactions.

As a general aspect of my research, within the group of Professor Michael Greenfield, 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 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 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 am investigating 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 reality have been observed. Geometry analysis and NMA have been applied to develop more accurate FFs parameters.

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 provide the conformational space for a peptide folding process. Since large-scale motion 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 the 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 find atomistic detail in the process of peptide folding at water-membrane interfaces, and also provides a proper perspective in understanding of biophysical characteristics in the peptide-membrane interactions.

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 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 – 7 semesters at URI

3- TA for courses: Chemical Kinetics and Reactor Design, Thermodynamic 2, Engineering Material, 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 interested in teaching:

1- Applied mathematics in chemical engineering

2- Thermodynamics

3- Mass transfer

4- Heat transfer

5- Molecular modeling