2019-20 MBTG Monthly Student Seminar Series

First Tuesday of each month. Student talk at 4:00pm, pizza and beer get-together at 5:00 pm; Leichtag 107. 
Date Trainee Title of Talk
Oct 1, 2019 Doug Zhang Design and Functionalization of Nucleic Acid Nanostructures
Nov 5, 2019 Mounir Fizari Restricted mobility of packaged DNA in phage phi29 assessed by single-molecule optical tweezers measurements
Dec 3, 2019 Elizabeth Porto Expanding the Scope of Base Editing for Precise and Therapeutically-Relevant Genome Engineering
Jan 7, 2020 Ryan Weeks Development of Novel Ratiometric Biosensors for Live Cell Sensing of Ras Activity
Feb 4, 2020 An Hieh

Transcriptional Pausing and Its Roles in Human mitochondria

Mar 3, 2020 Ruben Elias Study of Proline-rich Domain of ALIX Reveals Allovalent Interactions and Phosphorylation and Temperature Induced Reversible Amyloids
Apr 7, 2020 Hoang Nguyen TBD
May 5, 2020 Aileen Button TBD
Jun 2, 2020 Christine Stephen TBD

2020 MBTG Invited Seminar Speakers 

William DeGrado 

University of California San Francisco

"De novo design of function in water-soluble and membrane proteins"
Thursday, March 12, 2020 at 12pm
NSB Auditorium 1205
Hosted by Alex Hoffnagle

The de novo design of proteins with bespoke structures and functions critically tests our understanding of the underlying chemical processes.  Impressive progress has been made in the design of proteins that fold into predetermined three-dimensional structures, and in the design of proteins that engage in protein-protein interactions.  By contrast, the classical problem of designing proteins that tightly and specifically bind densely functionalized, flexible small molecules rich in polar atoms has proven very difficult.  We are using a fragment-based approach to design ligand-binding proteins:  First, the ligand of interest is deconvoluted into a collection of fragments.  In the second step, we use unsupervised learning methods to find the modes by which proteins interact with such fragments to assure they are efficiently sampled.  To design a ligand-binding protein, we construct a large number of target backbones, using parametric equations to define the backbone conformation.  The sequence of the binding site and the orientation of the target ligand within a backbone are next designed in a hierarchic set of computations. We begin by satisfying the most difficult interactions involving the ligand’s polar groups, which are need to be accommodated by highly directional hydrogen-bonded interactions.  The computation then progresses to optimize shape complementarity and to introduce hydrophobic interactions; in parallel, the core of the protein is designed within the same calculation to assure that the designed tertiary structure supports the precise positioning of the critical sidechains in the active site.  We demonstrate the success of this approach through the design of metallo-organic cofactors and a protein that binds the FDA-approved factor Xa-binding drug, apixaban. Crystal structures of the complexes confirm the designs and demonstrate the specificity of the design.  

            The second portion of the talk will focus on the design of very highly selective proton transporters.  The ability to move protons is an essential feature required for proteins to create and utilize proton gradients.  The proton pathways through which protons apparently travel generally contain water and polar sidechains, which provide a conduction path via the classical proton-hopping mechanism.  However, in the time-averaged high-resolution structures of proteins, the apparent conduction paths are often interrupted by regions with well-packed apolar sidechain.  Molecular dynamics calculations have suggested that protons might pass through such dry, apolar sectors by forming transient water-wires that are only transiently formed a small fraction of the time.  Such a mechanism would also explain how very high proton selectivity is maintained, because any other hydrated ion would be excluded from a strongly apolar sector.  To test this hypothesis we designed a series of transmembrane helical bundles with a single pore lined with  polar and apolar  sectors of varying lengths.  The proteins form proton-selective channels with 106-fold selectivity for protons over other ions. X-ray crystallography and molecular dynamics simulations support the underlying hypothesis.


Ting Wu

Harvard Medical School

Tuesday, June 9, 2020 at 12pm
NSB Auditorium 1205
Hosted by Quinn Cowan


2019-20 MBTG Journal Club

Third Tuesday of each month, 4:00 pm, NSB 3211
Date  Trainee Faculty Facilitator Paper Title 
Oct 15, 2019 Bryce Ackerman None Low-barrier hydrogen bonds in enzyme cooperativity
Jan 21, 2020 Sonjiala Hotchkiss Betsy Komives Engineering protein assemblies with allosteric control via monomer fold-switching
Feb 18, 2020 Josh Corpuz Kevin Corbett

Structure of the toxic core of a-synuclein from invisible crystals

Mar 17, 2020 Alex Hoffnagle
Apr 21, 2020 Quinn Cowan
May 29, 2020 Angel Payan

MBTG Special Seminars

Trainees are encouraged to attend the seminars listed below in addition to all other mandatory MBTG events:

TBD