NSF Org:	MCB Division of Molecular and Cellular Biosciences
Recipient:	MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Initial Amendment Date:	May 2, 2001
Latest Amendment Date:	May 2, 2001
Award Number:	0091001
Award Instrument:	Standard Grant
Program Manager:	Parag R. Chitnis MCB  Division of Molecular and Cellular Biosciences BIO  Directorate for Biological Sciences
Start Date:	June 1, 2001
End Date:	May 31, 2005 (Estimated)
Total Intended Award Amount:	$330,000.00
Total Awarded Amount to Date:	$330,000.00
Funds Obligated to Date:	FY 2001 = $330,000.00
History of Investigator:	Bruce Tidor (Principal Investigator) tidor@mit.edu
Recipient Sponsored Research Office:	Massachusetts Institute of Technology 77 MASSACHUSETTS AVE CAMBRIDGE MA  US  02139-4301 (617)253-1000
Sponsor Congressional District:	07
Primary Place of Performance:	Massachusetts Institute of Technology 77 MASSACHUSETTS AVE CAMBRIDGE MA  US  02139-4301
Primary Place of Performance Congressional District:	07
Unique Entity Identifier (UEI):	E2NYLCDML6V1
Parent UEI:	E2NYLCDML6V1
NSF Program(s):	MOLECULAR BIOCHEMISTRY
Primary Program Source:	app-0101
Program Reference Code(s):	9183, BIOT
Program Element Code(s):	116600
Award Agency Code:	4900
Fund Agency Code:	4900
Assistance Listing Number(s):	47.074

ABSTRACT

0091001
Tidor
An important goal of molecular biochemistry is a detailed understanding of how enzymes bind their ligands with correct affinity and specificity to catalyze appropriate reactions while not accelerating inappropriate ones. While there is clearly a key role for affinity in many molecular binding and recognition events, specificity is also essential in many biochemical contexts. For example, enzymes often must discriminate between correct substrates and closely related molecules. Likewise, there is a compelling literature implicating differential binding of transition state over substrate as a fundamental principle of enzyme function. While tremendous progress has been made in advancing our understanding of the molecular determinants of affinity and specificity, the current state of the art is still significantly incomplete. While rationalization of relative affinities and specificities is possible given high-resolution structural information, the knowledge obtained from such studies has been insufficient to allow for routine rational ligand design or enzyme engineering. New approaches are needed to expand our fundamental understanding in this crucial area. The project involves the study of two tRNA synthetases, the glutaminyl-tRNA synthetase (GlnRS) from Escherichia coli and the aspartyl-tRNA synthetase (AspRS) from the hyperthermophilic archaeon Pyrococcus kodakaraensis. Research activities include the application of current and novel approaches using theoretical and computational techniques to understand more thoroughly the molecular basis for ligand binding affinity and specificity by these highly evolved enzymes. Molecular mechanics, molecular dynamics, and continuum electrostatics will be used to analyze determinants of binding in the enzyme active sites and in the ligands. The research will expand our fundamental understanding of binding affinity and specificity by two tRNA-synthetase enzymes. The principles learned are expected to have broad applicability to enzymes and other molecular catalysts. They will contribute to the growing foundation that is essential to produce enabling technologies in the key areas of molecular design and enzyme engineering.

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