Transcript HIV-1 protease molecular dynamics of a wild

HIV-1 protease molecular dynamics of a wildtype and of the V82F/I84V mutant:
Possible contributions to drug resistance and
a potential new target site for drugs
Alexander L. Perryman, Jung-Hsin Lin and J. Andrew
McCammon. Protein Science 2004 13: 1108-1123
Presented by Ankit Garg
Problem: HIV-1 protease
 Virus is mutating
 Mutants are more drug-resistant than wild-type
 for one strain, resistance to a drug increased from
3.4% (1995-1998) to 12.4% (1999-2000)
 Resistance to multiple different drugs increased
from 1.1% to 6.2% in the same time period
 Comparing simulations of both the wild-type
and a mutant could lend insight into the cause
for drug resistance and ways to overcome it
Method: 22 ns simulations
 Simulation appropriate because indirect effects
are involved in drug resistance
 “If residue B has a hydrogen bond with a drug,
that is an example of a direct effect on the
drug; however, if residue X has interactions
that affect the position of that residue B, then
residue X has an indirect effect on the drug”
 Entire range of flap motion is visible in the nsec timeframe – this will be clear in next slide
The importance of flaps
 Flap dynamics emerged as a determining factor:
 Flap opening/closing affects association/disassociation
rates of drug – further evidence of this via NMR
 Flap motion also affects free energy barrier of
enzymatic reaction by controlling distance between the
substrate and the catalytic aspartate
Mutant vs Wild-type flaps
 Mutant flaps “curl”
faster and more
frequently
 Flap curling is a
precursor to flap
opening and closing
Mutant vs Wild-type flaps
 Mutant flaps
opened more
than the wildtype flaps
 Authors used
various
measures to
determine flap
openness
Flap opening and drug
resistance
 It is thought that
the larger and
more frequent
opening of flaps
in the mutant
encourages
dissociation of
the substrate,
hence causing
drug resistance
An interesting finding:
 Flap-to-asp
distance values
are anticorrelated
to Ear-to-Cheek
values
The Ear-Cheek
interface region could
potentially be targeted
by new allosteric
inhibitor drugs!
Proposal: “double
protease cocktails”
 Treat patients with original drug + a drug acting
on the Ear-Cheek interface
 Allosteric-Flap-Openers (AFOs)
 Pinch Ear-Cheek interface, forcing active site flaps
to open so they are not catalytically competent.
 Allosteric-Flap-Closers (AFCs)
 Expand Ear-Cheek interface, encouraging active
site flaps to stay closed, increasing their binding
affinities for the original drug
Discussion
 Have these recommendations been followed up on
experimentally?
 How do we know drug dissociation is being caused by
flap opening and closing, rather than a conformational
change to the binding site itself?
 The authors chose to look at the Ear-Cheek interface
primarily because it was physically close to the active
site. Could they be missing some other, more
important correlation? Should we be worried about
their approach in actively seeking a correlation with
that region’s morphology?