Serine proteases: An ab initio molecular dynamics study

Santis, Lorenzo De; Carloni, Paolo

doi:10.1002/(sici)1097-0134(19991201)37:4<611::aid-prot11>3.0.co;2-7

Cited by 30 publications

(30 citation statements)

References 44 publications

(69 reference statements)

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“…3B!. Similar approaches have shown to describe accurately the structural and dynamical properties of other enzymatic systems~Alber et al, 1998; De Santis & Carloni, 1999;Piana & Carloni, 2000!. Geometry optimization was carried out also for model I, using the direct inversion of the iterative subspace~DIIS! method~Pulay, 1980; Hutter et al, 1994!…”

Section: Calculationsmentioning

confidence: 99%

“…where q i represents the RESP~Cornell et al, 1993! atomic point charges of atom i with coordinates r i , following the procedure of our previous work~De Santis & Carloni, 1999;Piana & Carloni, 2000!. Charges on protein residues that are included in our quantum model have been set to zero.…”

Section: Calculationsmentioning

confidence: 99%

“…Detailed quantum mechanical treatments of molecular and electronic structure are emerging as tools for the prediction of molecular geometry, reaction paths of enzymatic transformations, electrostatic effects, and interpretations of spectroscopic probes of biomolecular environments at very accurate levels. Ab initio calculations are also increasingly being applied to systems of pharmaceutical relevance, helping to shed light on intricate and subtle aspects of substrate-and drug-enzyme intermolecular interaction~Cheney et al., 1988;Beveridge & Heywood, 1993;Perakyla & Pakkanen, 1995, 1996Beveridge, 1996;Alber et al, 1998;De Santis & Carloni, 1999;Piana & Carloni, 2000!. Here, we use ab initio quantum chemical methods to study the nature of the intermolecular interactions between HIV-1 RT and nucleosidic phosphate, which plays a major role in drug resistancẽ Zhang et al, 1994!…”

mentioning

confidence: 99%

“…Finally, it has already shown to reproduce accurately structural and dynamical properties of phosphate moieties~Alber et al, ! and of enzyme active sites~Alber et al, 1998De Santis & Carloni, 1999;Piana & Carloni, 2000!.…”

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confidence: 99%

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Ab initio molecular dynamics studies on HIV‐1 reverse transcriptase triphosphate binding site: Implications for nucleoside‐analog drug resistance

Alber

Carloni

2000

Protein Science

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Quantum-chemical methods are used to shed light on the functional role of residues involved in the resistance of HIV-1 reverse transcriptase against nucleoside-analog drugs. Ab initio molecular dynamics simulations are carried out for models representing the adduct between the triphosphate substrate and the nucleoside binding site. The triphosphate is considered either deprotonated or protonated at the g-position. Although the protonated form already experiences large rearrangements in the ps time scale, the fully deprotonated state exhibits a previously unrecognized low-barrier hydrogen bond between Lys65 and g-phosphate. Absence of this interaction in Lys65rArg HIV-1 RT might play a prominent role in the resistance of this mutant for nucleoside analogs~Gu Z et al., 1994b, Antimicrob Agents Chemother 38:275-281; Zhang D et al., 1994, Antimicrob Agents Chemother 38:282-287!. Water molecules present in the active site, not detected in the X-ray structure, form a complex H-bond network. Among these waters, one may be crucial for substrate recognition as it bridges Gln151 and Arg72 with the b-phosphate. Absence of this stabilizing interaction in Gln151rMet HIV-1 RT mutant may be a key factor for the known drug resistance of this mutant toward dideoxy-type drugs and AZT Shirasaka T et al

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Section: Calculationsmentioning

confidence: 99%

Section: Calculationsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Ab initio molecular dynamics studies on HIV‐1 reverse transcriptase triphosphate binding site: Implications for nucleoside‐analog drug resistance

Alber

Carloni

2000

Protein Science

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“…This approach has already revealed itself as a powerful tool to describe structure and bonding of rather large complexes representing substrate/enzymes adducts. [26][27][28][29][30] Methodology Model Complexes. Complex I was built from the ternary catalytic complex of HIV-1 RT (EC 2.7.7.49) with a substrate (dTTP) and the DNA-primer and template 24 (entry 1RTD in the Brookhaven Database 31 ) ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Cation-π versus OH-π Interactions in Proteins: A Density Functional Study

and

Carloni

2000

J. Phys. Chem. B

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Structure and bonding of a cation-π complex and an OH-π adduct are investigated using density functional theory with gradient-corrections for the exchange-correlation functional. Our calculations are carried out for two specific model complexes representing (i) the thymine/Arg 72 adduct in the ternary complex of HIV-1 reverse transcriptase (RT) with a DNA template primer and a deoxynucleoside triphosphate (Huang, H., et al. Science 1998, 282, 1669-1675 and (ii) the Tyr6-Thr13 adduct in µ-gluthatione transferase (µ-GST) (Xiao, G., et al. Biochemistry 1996, 35, 4753-4765). We find that electrostatic interactions play an important role and provide similar stabilization energies to the two π complexes. In HIV-1 RT, the π electronic density of thymine is essentially uneffected by the presence of the arginine guanidium group; on the contrary, tyrosine is significantly polarized by the interaction with the hydroxyl group and other groups present in the µ-GST enzyme. The influence of Thr13 induced-polarization on Tyr6 pK a is compared with that of other interacting groups at the active site.

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Influence of δ‐Functional Groups on the Enantiorecognition of Secondary Alcohols by Candida antarctica Lipase B

et al. 2008

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The selectivity of acetylation of delta-functionalized secondary alcohols catalyzed by Candida antarctica lipase B has been examined by molecular dynamics. The results from the simulation show that a delta-alcohol functionality forms a hydrogen bond with the carbonyl group of Thr 40. This interaction stabilizes the tetrahedral intermediate and thus leads to selective acetylation of the R enantiomer. A stabilizing interaction of the delta-(R)-acetoxy group with the peptide NH of alanine 282 was also observed. No stabilizing interaction could be found for the delta-keto functionality, and it is proposed that this is the reason for the experimentally observed decrease in enantioselectivity. From these results, it was hypothesized that the enantioselectivity could be restored by mutating the alanine in position 281 for serine. The mutation was made experimentally, and the results show that the E value increased from 9 to 120.

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Serine proteases: An ab initio molecular dynamics study

Abstract: In serine proteases (SPs) ,

Cited by 30 publications

References 44 publications

Ab initio molecular dynamics studies on HIV‐1 reverse transcriptase triphosphate binding site: Implications for nucleoside‐analog drug resistance

Ab initio molecular dynamics studies on HIV‐1 reverse transcriptase triphosphate binding site: Implications for nucleoside‐analog drug resistance

Cation-π versus OH-π Interactions in Proteins: A Density Functional Study

Influence of δ‐Functional Groups on the Enantiorecognition of Secondary Alcohols by Candida antarctica Lipase B

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