Gert Kiss

Mentors: Chaitan Khosla and Vijay Pande

Project Title: Protein Engineering through Molecular Simulations

Biography

I am a postdoc in the lab of Vijay Pande where I focus on the dynamic aspects of enzyme catalysis and on molecular recognition. I did my Ph.D. with Ken Houk at UCLA and interfaced with David Baker (UW) and Steve Mayo (Caltech) on several interesting protein design projects. For my undergraduate degree, I studied chemistry at the University of Heidelberg in Germany. In the evenings, if I'm not in lab, you'll most likely find me either at the Avery pool, or at the squash courts. Weekends I might break away on my Triumph for a couple of hours; PCH, La Honda, Skyline.

Research Summary

This project aims at building a platform for the routine production of natural products and analogues. The focus is on the biosynthetic pathway that is utilized by polyketide synthases (PKSs) to produce the backbones of polyketides - substances with interesting medicinal properties that have been shown to target atherosclerosis, bacteria, fungi, viruses, and cancers.

A major bottleneck in their production lies witin the involvement of an uncoupled set of synthetic organic chemistry steps for modifications to the initial building blocks (upstream), and of the polyketide backbone (downstream). Much too often, however, the synthetic organic augmentation becomes prohibitive. This can be problematic, particularly when it comes to stereo-, and regioselectivity, and the separation of racemic products. Instead, we aim to append engineered enzymes –– both upstream and downstream to the PKS cascade –– that can functionalize polyketide backbones with the desired stereo-, and regiospecificity in a ‘one-pot’ fashion.

Our strategy goes beyond the current limits of rational enzyme design by employing the latest developments in computational protein engineering and combining them with large scale physics based simulations and synthetic biology. Rational design, computational validation, and experimental testing are carried out in an iterative fashion to maximize their impact while keeping the experimental expenditure at a minimum. This close marriage between computational and experimental techniques is carried out in collaboration with the lab of Prof. Chaitan Khosla. Connecting these advanced rational approaches to aid in the design of molecules could have a broad impact on other CMAD-affiliated labs.