Chemistry Reference
In-Depth Information
crucial.for.many.biochemical.phenomena.that.take.place.in.the.living.cell. 40 .The.use.
of.Density.Functional.Theory.(DFT),.possibly.coupled.with.molecular.mechanics.or.
molecular.dynamics.methods,.may.help.to.overcome.most.of.these.issues. 35,39,40,48-52 .
In.the.irst.instance,.DFT.methods.represent.an.excellent.trade-off.between.accuracy.
and.computer.requirements,.particularly.suitable.for.the.investigation.of.biological.
systems. 35,40 .The.simple.principle.on.which.DFT.is.based.is.that.of.expressing.the.
total.energy.of.the.system.as.a.functional.of.the.electron.density. 53,54 .This.leads.to.
the.treatment.of.correlation.effects.at.a.lower.computational.cost.than.that.of.more.
rigorous.post-Hartree-Fock.methods..QM.(and.in.particular.DFT).methods.can.be.
coupled.with.molecular.mechanics.in.the.well-known.QM/MM.approaches. 55-58 .In.a.
typical.protocol,.a.relatively.small.region.of.the.entire.model,.e.g.,.the.active.site.of.
an.enzyme.or.the.solute.in.an.aqueous.solution,.is.described.at.the.DFT.level,.with.
the.remainder.being.treated.within.the.MM.level..Based.on.this.approach,.a.myriad.
of.studies.have.been.successfully.completed.in.recent.years. 35,36,39,40,44,51,52,59-65
In. this. review,. we. illustrate. some. examples. of. how. DFT. calculations. may. be.
employed. to. address. crucial. issues. of. biological. simulations.. Our. contribution. is.
clearly.limited.to.a.few.examples.taken.from.our.studies.and.does.not.cover.impor-
tant.studies.from.several.other.research.groups..For.other.surveys.on.this.topic.the.
reader.is.directed.to.the.following.references. 31,32,34,40,49,50,52
Our.focus.is.on.DFT.and.on.QM(DFT)/MM.methods.applied.to.metal-.containing.
biosystems.. First,. an. intriguing. example. of. solvation. effects. in. the. Yandulov. and.
Schrock.biomimetic.nitrogen.ixation.is.discussed. 24-30 .Second,.the.important.con-
tribution. played. by. QM/MM. calculations. for. macromolecules. such. as. DNA. and.
proteins.is.covered..In.particular,.examples.of.platinum-containing.anticancer.com-
pounds.interacting.with.DNA.fragments.are.proposed, 66-68 .as.well.as.the.reactivity.
of. speciic. zinc-containing. proteins.. Each. of. the. following. sections. describes. the.
limitations.as.well.as.the.potential.of.DFT.methods.with.the.overall.goal.of.convinc-
ing.the.reader.that.these.calculations.are.central.to.modern.biosciences.and.can.offer.
a.solid.complement.to.the.experimental.approach.
1.2   DENSITY FUNCTIONAL THEORY AND ITS 
APPLICATION TO BIOLOGICAL SYSTEMS
This. section. illustrates. the. basic. elements. of. the. theoretical. tools. employed. in. the.
selected.examples.discussed.below..It.is.clearly.beyond.our.aims.to.propose.a.rig-
orous. description. of. DFT-based. methods,. which. is. already. available. in. many. text.
books 53,54,69,70 .and.in.recent.reviews. 32,34,35,40,42,48,50-52
The.electron.correlation,.i.e.,.the.quantum.interaction.of.electrons,.is.central.to.
achieving.a.quantitative.theoretical.description.of.natural.processes,.especially.those.
for. which,. for. instance,. hydrophobic. forces,. weak. H-bonding,. transition. metals,.
covalent.bond.breaking/forming.are.important..The.most.rigorous.approach.to.take.
into.account.this.physical.feature.is.the.use.of.post-Hartree-Fock.(post-HF).meth-
ods,.such.as.Møller-Plesset.or.coupled.cluster.methods..Successful.applications.of.
these.two.systems.of.biological.relevance.are.reviewed.in.references. 32,42,43 .However,.
biological.systems.often.contain.many.heavy.atoms,.and.high-level.correlated.meth-
ods. become. rapidly. prohibitive. in. computer. time. and. resources.. DFT,. in. contrast,.
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