First Principles DFT Studies of Metal-Based Biological and Biomimetic Systems - Metallic Systems: A Quantum Chemist's Perspective - page 2

exceptions,. the. metal. ion. of. choice. in. the. enzymes. involved. in. the. biochemistry.
of.nucleic.acids,.while.potassium.is.close.to.DNA.in.the.cell. 8 .Zinc.plays.a.struc-
tural.and.catalytic.role.in.a.large.number.of.proteins,.enzymes,.and.transcription.
factors. 9,10 . Manganese-containing. enzymes. have. a. wide. range. of. functionalities,.
especially.in.redox-active.biomolecules.such.as.manganese.catalase.and.superox-
ide.dismutase. 11
Not.only.are.metal.elements.vital.in.many.biological.phenomena,.but.they.can.
also. be. exploited. in. therapeutics:. medicinal. applications. have. been. known. for.
almost. 5000. years. 1 . The. development. of. modern. medicinal. inorganic. chemistry.
has.been.fueled.by.the.serendipitous.discovery.of.cisplatin.as.an.anticancer.agent.
at. the. beginning. of. the. 1960s. 12 . Since. then,. the. application. of. metal-based. drugs.
for. therapeutics. has. experienced. tremendous. and. continuous. growth. 13 . Nowadays,.
research. is. fervent. with. the. aim. of. providing. effective. anticancer,. antibiotic,. anti-
bacterial,. antiviral,. and. radio-sensitizing. agents. exploiting. the. special. features. of.
metal.elements. 1 .Besides.platinum,.whose.complexes.are.probably.the.best-studied.
metal-based.compounds.in.therapeutics,.many.other.metal.complexes.are.currently.
being. used,. tested,. or. designed. 13 . A. great. hope. lies. in. ruthenium. compounds. as. a.
valid. alternatives. to. cisplatin. for. the. treatment. of. cancer. 14 . Examples. of. the. latter.
include.NAMI-A, 15 .ICR, 16 .and.Salder's.compounds. 17,18 .Furthermore,.complexes.of.
V, 19 .Au, 20 .Rh, 21 .Ir, 22 .and.Cu 23 .are.considered.potentially.active.against.tumors.fea-
turing. a. diversity. of. mechanisms. of. action.. Another. important. ield. of. bioscience.
in.which.metals.can.play.an.important.role.is.the.research.for.artiicial.compounds.
that.can.mimic.biosystems..One.of.the.most.recent.and.striking.examples.of.this.is.
the.molybdenum-based.catalyst.of.Yandulov.and.Schrock,.which.promotes.nitrogen.
ixation.under.mild.conditions. 24-30
The. impressive. improvements. achieved. by. theoretical. methods. have. provided.
an. important. support. to. biosciences. in. many. ields. 31-34 . In. particular,. the. theoreti-
cal.investigation.of.biological.systems.has.now.achieved.the.necessary.maturity.to.
complement. the. experimental. approach.. For. example,. quantum. mechanical. (QM).
calculations.are.applied.to.drug.design.and.to.the.prediction.of.spectroscopic.phe-
nomena. 35-41 . The. advantage. of. QM. calculations. with. respect. to. force. ields. based.
methods. is. that. they. account. for. quantum. electronic. effects. and. can. therefore.
describe.bond.forming/breaking.phenomena,.polarization.effects,.and.charge.trans-
fer.along.with.an.accurate.estimation.of.reaction.(free).energies.
Unfortunately,. the. investigation. of. systems. of. biological. relevance. with. irst.
principles. methods. is. not. straightforward. as. many. issues. render. their. application.
rather.awkward,.among.which.the.timescale.problem.is.perhaps.the.most.dificult.to.
solve. 32,42,43 .A.complete.QM.description.of.biomolecules,.with.the.exception.of.few.
remarkable.instances, 44,45 .is,.in.fact,.beyond.the.possibility.of.present.theories.and.
computer.power..First,.biological.processes.occur.in.aqueous.solution.(and/or.mem-
branes),.i.e.,.to.achieve.an.accurate.description.of.the.system,.solvation.effects.cannot.
be.neglected..However,.modeling.solvation.is.one.of.the.most.critical.challenges.of.
QM.calculations, 40,46-48 .due.to.the.size.of.the.system,.the.large.number.of.degrees.of.
freedom.and.the.effects.of.counter.ions..Second,.most.biological.phenomena.occur.
around.300.K,.and.temperature.effects.should.be.taken.into.account..A.further.com-
plication. is. the. dynamical. effects. on. both. short. and. long. time. scales. that. become.