Overview

We use computer simulations and experiments to study the organization of cell signaling components, interfacial interactions and allostery to aid in the development of treatments for unsolved health challenges. Our special focus is on the Ras family of lipid-modified enzymes that regulate a variety of cell signaling pathways and whose malfunction leads to many forms of cancer and developmental disorders. The need for novel therapeautic agents that stop signaling through defective Ras is urgent. We contribute to the search for such agents by studying Ras at the atomic, molecular and supramolecular levels of detail using multi-scale molecular simulations and collaborative cell-biological and biophysical experiments. We are particularly interested in understanding how dynamics and lateral distribution of Ras and related G-proteins on membrane surfaces affect their ability to functionally interact with other proteins. Other interests of the group include modeling transient signaling complexes and interaction between specific drugs and phospholipids

Research Interests

Dynamics of Ras proteins in solution and in membrane

Simulations have played a key role in elucidating the dynamics of Ras proteins in the aqueous and membrane environments (see our recent review on this topic). We apply classical and advanced molecular dynamics simulations on the isolated catalytic domain in water [e.g. 1], the lipid-anchor [e.g. 2] and the full-length Ras in bilayers of various lipid composition [3,4]. Our current focus is on K-Ras, which is the most frequently mutated Ras isoform in human cancers and developmental disorders. Ongoing projects revolve around the question of how somatic and genetic mutations may alter the population of conformational states and oligomerization behavior of K-Ras, and how these may affect interaction with effectors or modulators.

Organization of Ras proteins in membrane domains

Our work on membrane-organization of Ras proteins involves studying various lipid bilayer models using atomically detailed simulations [e.g. 1,2] and large-scale coarse-grained simulations of Ras-membrane complexes [3,4]. Previous simulations led to important insights into the physical basis for clustering and non-overlapping distribution of different Ras proteins in membrane domains. In particular, the nature of the lipid-modification was found to dictate the specific lateral organization of different Ras proteins on the membrane and that cholesterol modulates lipid domain stability and thereby the stability of Ras nanoclusters. Surface-bound proteo-oligomers can also be used to probe some of the mechanisms by which membrane curvature might be generated and/or maintained. However, a number of technical challenges remain to be solved in order to accurately and fully model oligomers of surface-bound Ras and other lipid-modified proteins [5], which is the object of our current focus.

Targeting an elusive foe

As part of a broader effort to developing anti-Ras therapeutics, we leverage insights emerging from the projects described above for the design of inhibitors that directly act on Ras. Our previous studies provided the initial clues about the allosteric nature of Ras and the role of conformational selection for its function [1,2,3,4,5,6]. This led us to contemplate the potential druggability of Ras at the time when this was thought hopeless [7]. Spurred in part by findings from large-scale genomic studies that the KRAS gene remains to be the main culprit in many forms of cancer, Ras is now back in the forefront of the search for new anti-cancer therapeutics. Our contribution to this effort includes the identification of novel allosteric ligand binding sites and prediction of small-molecule ligands that might bind to these sites [8,9]. Moreover, working with cell biologists and pharmacologists, we showed for the first time that nucleotide exchange factors are required for oncogenic Ras signaling and inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras [9]. Our current effort in the search for isoform-selective Ras inhibitors includes developing methods to incorporate membrane into our dynamics-guided, ensembled-based drug-design scheme.

Interaction of NSAIDs with micelles and bilayers

We would like to understand the physical basis for the ability of common non-steroidal anti-inflamatory drugs (NSAIDs), such as aspirin, to cause gastrointestinal injury through their detrimental effect on surface membranes. This effect appears to be exacerbated by bile salts and reduced or eliminated by conjugating NSAIDs with phosphatidylcholines (PCs). We study the surface behavior, morphology and size of micellar particles that appear during simulations of binary and ternary mixtures of NSAIDs and bile salts with different PCs. Initial results suggest that NSAIDs can form potentially cytotoxic aggregates with bile acids, and may alter the normal physiologic balance between bile acids and PCs [e.g.1,2].

Lab Members

		worker
		   Alemayehu Gorfe
		   PhD (Biochemistry, University of Zurich).
		   Principle Investigator
	
		worker
		 Priyanka P. Srivastava
		 PhD(Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur (IITK))
		 Postdoctoral Fellow: Allostery and drug-membrane interactions
	
		worker
		  Abdallah Sayyed-Ahmad
	     	  PhD(Chemistry, Indiana University) 
		  Research Scientist:Electrostatics and biomolecular recognition
		
		worker
		  Michael McCarthy
		  MSc (University of Texas Health Science Center at Houston)
		  Graduate Student: Structure-based drug design
	
		worker
		 Amit Gupta
		 PhD (Biological Sciences, CDRI/AcSIR, New Delhi, India)
		 Postdoctoral Fellow: Protein-ligand interactions and drug discovery
	
		worker
		 Xubo Lin
		 PhD (Biomaterials, Southeast University Nanjing, China)
		 Postdoctoral Fellow:Dynamics of membrane and membrane proteins
	
		worker
		 Suparna Sarkar-Banerjee
		 Expecetd PhD (Biochemistry, CSIR-Indian Institute of Chemical Biology)
		 Research Assistant:Biophysical and Cell assays
	
		worker
		 John Rogers
		 BSc (Chemical Engineering, Texas AM University)
		 SRP: CADD
	
		worker
		 Jonathan Getahun
		 Undergraduate (Neuroscience, Johns Hopkins University)
		 SRP: TBD
	
		worker
		   Nabina Paudyal
		   Masters in Physics from University of Akron, Akron, Ohio
		   SRP: TBD

News

May 2015
Apirl 2015:
    Welcome to our new colleagues Amit Gupta and Suparna Sarkar!
March 2015:
    Congratulations to Zhenlong Li, who is now Research Associate at Cornell Univesity.
January 2015:
October 2014:
    • Abdallah Sayyed-Ahmad rejoins our group as a Research Scientist. Welcome!
    • Xubo Lin joins our group for his postdoctoral training. Welcome!
  • June 2014:
    May 2014:
    • Congratulations to Priyanka Prakash on winning -- for the third year in a row -- an award for her poster presentation at the 18th Sealy Center Structural Biology Symposium in Galveston, TX.
    • We welcome Michael McCarthy, who joins the group for his PhD thesis on structure-based drug design combining experimental and computational approaches.
    • Harrison Hocker accepted a position at GE Capital in New Orleans, LA.
  • March 2014:
      Michael McCarthy joins our group for his third rotation. Welcome!
    February 2014:
      Harrison Hocker successfully defended his PhD thesis on 2/24/2014.Congratulations!
    November 2013:
      Congratulations to Priyank Prakash on winning second place award in the Keck Annual Research Confernece poster competition.
    October 2013:
      Congratulations to Harrison Hocker on winning third place award in the GSEC poster competition at the Medical School Retreat.
    July 2013:
      Alex Gorfe profiled on the American Society of Biochemistry and Molecular Biology website
    June 2013:
      Our paper highlighted in Science-Business eXchange – Nature (see link and Box 1 in here).
    May 2013:
    • Alex Gorfe received 2012-2013 Dean's Teaching Excellence Award 
    • Nandini Rambahal successfully defended her masters thesis on May 28. Congratulations!
    • Congratulations to Priyanka Prakash and Zhenlong Li on their first and second place awards for their poster presentation at this years Sealy Center Structure Biology Symposium in Galveston.
    April 2013: 
    • Congratulations to Harrison Hocker on his second place win for best graduate student oral presentation at this year's CRB rereat
    • Congratulations to Zhenlong Li on his second place win for best postdoc oral presentation at this year's CRB retreat.
    March 2013:
      Drew Dolino joins our group as rotation student. Welcome Drew!
    January 2013:
    • Congratulations to Lorant Janosi, a former postdoc in the lab, on his appointment as Senior Researcher at the National Institute for Research and Development of Isotope and Molecular Technologies of Romania.
    • Kelsey Maxwell joins our group for her second rotation. Welcome Kelsey!
    • Congratulations to Harrison and Nandini on winning GSBS travel awards to present their work at the upcoming American Chemical Society National Meeting in New Orleans.
    December 2012:
    Congratulations to Zhenlong on his UTHealth Innovation for Cancer Research Postdoctoral Fellowship award (sponsored by CPRIT).

    November 2012:
      Congratulations to Nandini on winning a travel award from the Biophysical Society to present her work at the next BPS meeting in Philadelphia.
    October 2012:
      Congratulations to Zhenlong on winning a prize for his poster presentation at the 22nd Keck Annual Research Conference in Houston.
    September 2012:
      Congratulations to Priyanka on her postdoctoral fellowship award from the Computational Cancer Biology Training Program (sponsored by CPRIT).
    August 2012:
    • Congratulations to Nandini on winning a fellowship from the NBCR Summer Institute and her third place poster award.
    • An RO1 award from the NIH for our "protein nanoclustering" project.
    June 2012:
    April 2012:
      Congratulations to Hualin, Zhenlong and Priyanka who have won awards for their poster presentation at the Sealy Center Structural Biology Symposium in Galveston!
    Aug 2011:
      Hualin Li joins us as postdoctoral fellow. Welcome Hualin!
    May 2011:
    • Priyanka P. Srivastava successfully defended her thesis at IIT Kanpur.
    • Priyanka rejoins our group as a postdoctoral fellow. Welcome Pri!
    • Welcome to Nandini Maharaj, who joins our group as a graduate student.
    March 2011:
      Congratulations to Harrison Hocker on winning the GCC-Pharmacological Sciences Training Program grant.
    Feruary. 2011:
      We welcome Ming Han to the group.
    Jan. 2011:
      We welcome Zhenlong Li to the group.
    Oct. 2010:
      We welcome Priyanka P. Srivastava to the group.
    Sept. 2010:
      Congratulations to Lorant Janosi, who has moved on to the University of Cagliari with the prestigious Marie Curie Fellowship.
    Aug. 2010:
      Congratulations to Abdallah Sayyed-Ahmad, who has moved on to his new position as Assistant Professor of Physics at Birzeit University.