PMID- 22239286
OWN - NLM
STAT- MEDLINE
DCOM- 20120612
LR  - 20211021
IS  - 1520-5207 (Electronic)
IS  - 1520-6106 (Print)
IS  - 1520-5207 (Linking)
VI  - 116
IP  - 6
DP  - 2012 Feb 16
TI  - Interaction of I50V mutant and I50L/A71V double mutant HIV-protease with 
      inhibitor TMC114 (darunavir): molecular dynamics simulation and binding free 
      energy studies.
PG  - 1884-900
LID - 10.1021/jp2074804 [doi]
AB  - In the present work, the binding of inhibitor TMC114 (darunavir) to wild-type 
      (WT), single (I50V) as well as double (I50L/A71V) mutant HIV-proteases (HIV-pr) 
      was investigated with all-atom molecular dynamics (MD) simulations as well as 
      molecular mechanic-Poisson-Boltzmann surface area (MM-PBSA) calculation. For both 
      the apo and complexed HIV-pr, many intriguing effects due to double mutant, 
      I50L/A71V, are observed. For example, the flap-flap distance and the distance 
      from the active site to the flap residues in the apo I50L/A71V-HIV-pr are smaller 
      than those of WT- and I50V-HIV-pr, probably making the active site smaller in 
      volume and closer movement of flaps. For the complexed HIV-pr with TMC114, the 
      double mutant I50L/A71V shows a less curling of the flap tips and less 
      flexibility than WT and the single mutant I50V. As for the other previous 
      studies, the present results also show that the single mutant I50V decreases the 
      binding affinity of I50V-HIV-pr to TMC, resulting in a drug resistance; whereas 
      the double mutant I50L/A71V increases the binding affinity, and as a result of 
      the stronger binding, the I50L/A71V may be well adapted by the TMC114. The energy 
      decomposition analysis suggests that the increase of the binding for the double 
      mutant I50L/A71V-HIV-pr can be mainly attributed to the increase in electrostatic 
      energy by -5.52 kacl/mol and van der Waals by -0.42 kcal/mol, which are canceled 
      out in part by the increase of polar solvation energy of 1.99 kcal/mol. The 
      I50L/A71V mutant directly increases the binding affinity by approximately -0.88 
      (Ile50 to Leu50) and -0.90 (Ile50' to Leu50') kcal/mol, accounting 45% for the 
      total gain of the binding affinity. Besides the direct effects from the residues 
      Leu50 and Leu50', the residue Gly49' increases the binding affinity of 
      I50L/A71V-HIV-pr to the inhibitor by -0.74 kcal/mol, to which the electrostatic 
      interaction of Leu50's backbone contributes by -1.23 kcal/mol. Another two 
      residues Ile84 and Ile47' also increase the binding affinity by -0.22 and -0.29 
      kcal/mol, respectively, which can be mainly attributed to van der Waals terms 
      (DeltaT(vdw) = -0.21 and -0.39 kcal/mol).
FAU - Meher, Biswa Ranjan
AU  - Meher BR
AD  - Computational Chemistry Laboratory, Department of Natural Sciences, Albany State 
      University, Albany, Georgia 31705, USA.
FAU - Wang, Yixuan
AU  - Wang Y
LA  - eng
GR  - SC3 GM082324-02S1/GM/NIGMS NIH HHS/United States
GR  - SC3 GM082324/GM/NIGMS NIH HHS/United States
GR  - R25 GM071415-07/GM/NIGMS NIH HHS/United States
GR  - SC3GM082324/GM/NIGMS NIH HHS/United States
GR  - 3SC3GM082324-02S1/GM/NIGMS NIH HHS/United States
GR  - 2R25GM071415/GM/NIGMS NIH HHS/United States
GR  - SC3 GM082324-04/GM/NIGMS NIH HHS/United States
GR  - R25 GM071415/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, American Recovery and Reinvestment Act
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120203
PL  - United States
TA  - J Phys Chem B
JT  - The journal of physical chemistry. B
JID - 101157530
RN  - 0 (HIV Protease Inhibitors)
RN  - 0 (Sulfonamides)
RN  - EC 3.4.23.- (HIV Protease)
RN  - YO603Y8113 (Darunavir)
SB  - IM
MH  - Amino Acid Substitution
MH  - Darunavir
MH  - HIV Protease/*chemistry/genetics/metabolism
MH  - HIV Protease Inhibitors/*chemistry/metabolism
MH  - HIV-1/drug effects/*enzymology
MH  - Humans
MH  - Hydrogen Bonding
MH  - *Molecular Dynamics Simulation
MH  - Mutation
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - Sulfonamides/*chemistry/metabolism
MH  - Thermodynamics
PMC - PMC3288396
MID - NIHMS349892
EDAT- 2012/01/14 06:00
MHDA- 2012/06/13 06:00
PMCR- 2012/02/28
CRDT- 2012/01/14 06:00
PHST- 2012/01/14 06:00 [entrez]
PHST- 2012/01/14 06:00 [pubmed]
PHST- 2012/06/13 06:00 [medline]
PHST- 2012/02/28 00:00 [pmc-release]
AID - 10.1021/jp2074804 [doi]
PST - ppublish
SO  - J Phys Chem B. 2012 Feb 16;116(6):1884-900. doi: 10.1021/jp2074804. Epub 2012 Feb 
      3.