First Principles DFT Studies of Metal-Based Biological and Biomimetic Systems - Metallic Systems: A Quantum Chemist's Perspective - page 21

long-range.electrostatics.of.the.MβL.scaffold..This.is.also.indirectly.conirmed.by.
the.results.obtained.from.classical.MD.simulations.of.different.β-lactam.antibiotics.
docked. at. the. CcrA. binding. pocket. (Scheme. 1.1,. Figure. 1.6). 192,194,195 . The. reaction.
coordinates. for. these. additional. adducts. are. always. relatively. short. (3.2(±2). Å. for.
IMI.binding.and.3.5(±2).Å.for.BPC)..This.is.consistent.with.the.fact.that.both.are.
eficiently.hydrolyzed.by.CcrA.and.BcII..The.key.interactions.of.the.bicyclic.core.
at.the.catalytic.cleft.are.still.preserved..More.importantly,.the.catalytic.water.mol-
ecule.(WAT).is.buried.at.the.cleavage.site.in.an.equivalent.position,.as.found.for.the.
adducts.complexed.with.cefotaxime.
These.common.elements.are.lexible.enough.to.accommodate.different.substrates.
and.elicit.a.broad.spectrum.activity.in.MβLs.based.on.a.similar.water-assisted.hydro-
lysis.mechanism.generally.plausible.for.penicillins,.cephalosporins,.and.carbapen-
ems..They.might.also.provide.a.rationale.as.to.why.monobactams.such.as.aztreonam.
that. lack. the. common. β-lactam. bicyclic. core. and. carboxylate. are. not. eficiently.
hydrolyzed.by.MβLs.
In.summary,.our.studies. of.MβL.catalysis.allow.us.to.suggest. that.a.Zn-bound.
water.(WAT.in.Figures.1.6,.1.7,.and.Scheme.1.2).turns.out.to.be.a.common.and.cru-
cial.chemical.feature.across.B1.MβLs..The.carboxylate.group.present.in.all.β-lactam.
antibiotics.stabilizes.WAT.at.the.active.site.upon.binding.so.that.the.water/β-lactam.
entity.should.be.considered.as.the.favorite.template.for.the.design.of.new.inhibitors..
These. results. also. point. to. the. crucial. role. of. the. Zn. in. the. second. metal-binding.
site.(Zn2),.which.stabilizes.the.negative.charge.developed.at.β-lactam.nitrogen.upon.
nucleophilic.attack..This.functional.advantage.is.evident.in.the.mechanism.of.di-Zn.
B1.MβLs.and.is.completely.missing.in.mono-Zn.species.which.are.indeed.character-
ized.by.low-eficiency.turnover.and.step.wise.mechanisms..This.may.suggest,.along.
with. recent. kinetic. indings, 199 . that. at. low. concentrations. of. zinc. equally. eficient.
catalysis.is.achieved.when.the.metal.ion.is.accommodated.in.the.second.metal.site.
1.4 GENERAL CONCLUSIONS
In.this.contribution,.we.have.briely.discussed.selected.examples.of.irst.principles.
DFT.and.QM/MM.studies.of.biosystems.for.which.metal.centers.play.a.pivotal.role..
First,.we.showed.that.even.a.relatively.simple.system.such.as.a.molybdenum-based.
catalyst.of.nitrogen.ixation.may.represent.a.tremendous.scientiic.challenge..Many.
DFT. functionals. failed. in. reproducing. reaction. energies. derived. from. experiment..
A.careful.choice.of.the.model.and.inclusion.of.solvation.effects.led.us.to.a.drastic.
improvement.of.the.theoretical.description.of.the.entire.reaction.
Second,.we.used.extensive.irst.principles.calculations.to.characterize.the.effect.
of.DNA.platination.with.two.speciic.platinum-based.anticancer.drugs,.i.e.,.cisplatin.
and.diplatin..Our.indings.provide.a.clear.rationale.for.the.improved.cytotoxic.activ-
ity.of.these.compounds.in.cell.lines.that.are.instead.resistant.to.cisplatin..Finally,.we.
provided.insights.into.the.role.of.zinc.for.the.mechanism.of.action.of.β-lactamases.
by.a.combination.of.classical.MD.and.QM/MM.approaches..In.summary,.we.con-
clude.that.irst.principles.calculations,.despite.their.limitations.(the.timescale.prob-
lem.being.the.most.dificult.to.address),.are.central.for.the.investigation.of.biological.
systems.in.which.metal.centers.often.play.a.pivotal.role.