2

Computational Studies On Schiff Base Formation: Implications For The Catalytic Mechanism Of Porphobilinogen Synthase.

Edvin Erdtman1,Eric A. C. Bushnell,2 James W. Gauld2 and Leif A. Eriksson1,3[*]

1 School of Science and Technology, Örebro Life Science Center and Modeling and Simulation Research Center, Örebro University, Örebro, Sweden

2 Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada

3 School of Chemistry, NUI Galway, Galway, Ireland

Supporting Information

(Tables S1 and S2; Total Pages: 43)


Table S1. Relative Activation energies (kcal mol–1) For Formation of Schiff Bases By Reaction of Methylamine With a Variety of Substrate Analogs, With and Without Catalysts.

Catalyzing molecule(s) / Substrate analog / Activation energy for carbinolamine formation / Rearrangements
/ Activation energy of Schiff base formation / Ref
Eel / ΔGaq298 / Eel / ΔGaq298 / Eel / ΔGaq298
Neutral / None / Formaldehyde / 26.8 / 20.0 / 2.5c / 3.4c / 55.2 / 54.4 / 7
None / Acetaldehyde / 32.1 / - / 6.1c / - / 53.8 / - / 8
None / Acetone (AM) / 38.87 / 36.64 / 5.15c / 3.86c / 53.14 / 48.68 / *
None / 5ALA (5-M) / 24.20 / 21.59 / 5.66c 2.17a / 2.3 1c 6.59a / 26.58 / 14.09 / *
1 H2O / Formaldehyde / 9.0 / 6.1 / - / - / 33.2 / - / 7
1 H2O / Acetaldehyde / 12.2 / - / - / - / 30.8 / - / 8
1 H2O / Acetone (AMW) / 18.28 / 18.13 / 10.33c / 7.80c / 29.41 / 26.24 / *
2 H2O / Formaldehyde / 2.6, 2.2 / 3.5, 4.6 / - / - / 26.7 / - / 7
Protonated / None / Formaldehyde / - / - / - / - / 34.4 / 39.8 / 7
None / Acetaldehyde / - / - / - / - / 32.7 / - / 8
None / 5ALA (5-MH+) / 31.06 / 22.32 / 6.24a 8.18b 10.98c / 5.04a 6.01b 9.04c / 10.13 / 8.98 / *
1 H2O / Formaldehyde / - / - / - / - / 21.0 / 24.0 / 7
1 H2O / Acetone (AMWH+) / 28.09b 2.10†† / 28.02b
2.28†† / 1.78a / 0.13a / 22.36 / 21.33 / *
2 H2O / Formaldehyde / - / - / - / - / 16.2 / 15.3 / 7
1 MA / Acetone (A2MH+) / 19.59†
2.44†† / 16.18†
5.99†† / 3.15 d 1.42b 8.87a 1.46c / 6.02d 0.96b 4.94a 0.63c / 3.61 / 7.52 / *
1 MA / Aminoacetone (Aa2MH+) / 31.30 / 24.32 / 2.43b 9.14c / 2.88b 4.16c / 4.87 / 6.35 / *
1 MA / 5ALA (5-2MH+) / 32.17 / 26.26 / 3.19b 10.61c / 2.22b 5.49c / 4.73 / 6.05 / *
1 H2O, 1 MA / Acetone (A2MWH+) / 18.83†
6.53 †† / 20.13†
7.67†† / 17.63b 6.02c / 14.23b 1.42c / 2.51 / 6.29 / *
*This work, †Compared to reactant complex, ††Compared to active complex. Rearrangements: arotation, bproton transfer, camine inversion, dmovement.

Table S2. Cartesian x,y,z coordinates of the optimized structures of each species noted in the text.

System: 5-2MH+

AC5-2MH+

C 0.254878 -2.384756 -0.537597

C -0.318988 -0.987926 -0.306625

C -1.823167 -0.899679 -0.213901

N 1.687052 -2.348508 -0.870909

O 0.421504 -0.017682 -0.215076

C -2.347519 0.438937 0.298390

H -0.359804 -2.899359 -1.290143

H 0.121402 -2.946951 0.395754

H 2.710299 -1.061027 0.075535

H 2.062382 -3.294733 -0.842051

H 1.804659 -2.031575 -1.832748

H -2.196389 -1.732575 0.395968

H -2.226421 -1.099624 -1.217142

N 3.360613 -0.401667 0.578055

H 4.312070 -0.595671 0.261453

C 3.254445 -0.575449 2.055604

H 3.493088 -1.603744 2.330703

H 2.232745 -0.342156 2.355988

H 3.944733 0.106212 2.554241

H 3.102729 0.622354 0.298100

H 1.602693 2.015711 -0.216471

N 2.603309 2.172046 -0.093946

C 3.188358 2.731459 -1.335382

H 4.258049 2.900714 -1.188554

H 3.063553 2.011487 -2.148517

H 2.726183 3.676852 -1.639078

H 2.697535 2.847864 0.662680

C -3.855102 0.531208 0.170929

H -2.072561 0.610438 1.344406

H -1.912183 1.271224 -0.265876

O -4.332020 1.638210 0.777816

O -4.557243 -0.269289 -0.408564

H -5.296926 1.658790 0.651442

TS15-2MH+

C 1.992631 -2.031024 0.117024

C 0.927297 -0.974972 -0.331337

C -0.492872 -1.266638 0.081396

N 3.112506 -1.814782 -0.856478

O 1.217711 -0.423454 -1.422789

C -1.498353 -0.189134 -0.315351

H 1.592656 -3.038888 -0.014148

H 2.334892 -1.916201 1.143736

H 3.965157 -1.441183 -0.439858

H 3.354414 -2.644798 -1.398292

H 2.592144 -1.057259 -1.488461

H -0.542869 -1.490041 1.151415

H -0.763455 -2.203524 -0.426297

N 1.373795 0.556448 1.087036

H 2.364102 0.755440 0.944556

C 1.093553 0.412696 2.528219

H 1.594017 -0.473448 2.931393

H 0.018090 0.295576 2.677911

H 1.424656 1.282930 3.106420

H 0.876348 1.389391 0.709328

H -0.846954 3.134016 -0.111735

N 0.142857 3.153577 0.127868

C 0.922658 3.589977 -1.051716

H 1.977876 3.671630 -0.774914

H 0.837617 2.834599 -1.837413

H 0.602490 4.555985 -1.460561

H 0.226057 3.848836 0.867795

C -2.924391 -0.657319 -0.108215

H -1.348835 0.735331 0.249937

H -1.377490 0.076855 -1.371559

O -3.802405 0.350127 -0.299834

O -3.253704 -1.786489 0.184167

H -4.700966 -0.004925 -0.180703

IM15-2MH+

C 1.343913 -2.360826 -0.133452

C 0.649431 -0.987956 -0.292211

C -0.849587 -1.069477 -0.024442

N 2.786620 -2.208030 -0.363080

O 0.861642 -0.461940 -1.575097

C -1.635466 0.214367 -0.302884

H 0.876492 -3.042203 -0.851078

H 1.146515 -2.764167 0.864206

H 3.344568 -2.624688 0.375460

H 3.090991 -2.641495 -1.229530

H 1.765351 -0.670347 -1.863299

H -1.026975 -1.410467 0.999856

H -1.236463 -1.865022 -0.668312

N 1.369044 -0.001979 0.652888

H 2.364591 -0.205083 0.474963

C 1.104090 -0.087652 2.119086

H 1.275720 -1.100797 2.483233

H 0.075029 0.205418 2.322826

H 1.781566 0.598191 2.630479

H 1.199758 1.015920 0.317906

H 0.707803 2.633102 -1.105533

N 1.084742 2.668321 -0.158613

C 2.395236 3.365927 -0.174397

H 2.782009 3.431943 0.845607

H 3.103886 2.789405 -0.774741

H 2.336814 4.377847 -0.588424

H 0.417277 3.219358 0.379929

C -3.113133 0.030168 -0.007295

H -1.287938 1.059801 0.303830

H -1.527610 0.522873 -1.347378

O -3.811241 1.144978 -0.306889

O -3.611586 -0.976162 0.445962

H -4.749638 0.979917 -0.106592

TS2a5-2MH+

C 1.424081 -2.269057 -0.085217

C 0.717430 -0.891916 -0.189872

O 0.981558 -0.337820 -1.463059

C -0.791907 -1.041374 0.001968

N 1.336331 0.089841 0.793156

C 0.988780 -0.050027 2.230072

H 0.875248 -2.967010 -0.723036

H 1.358680 -2.652106 0.938989

N 2.811421 -2.139369 -0.549873

H 1.139527 1.348191 0.295517

H 2.346885 -0.042343 0.689600

C -1.616658 0.231374 -0.198558

H -1.127990 -1.786635 -0.723891

H -0.998931 -1.473003 0.986366

H 1.627783 0.619295 2.810751

H -0.050922 0.236738 2.392506

H 1.133037 -1.070654 2.596145

H 0.820534 2.195127 -1.253322

N 1.031303 2.457441 -0.287988

C 2.273905 3.278248 -0.221789

H 2.476082 3.536686 0.818935

H 3.105822 2.691490 -0.615176

H 2.173983 4.193964 -0.807724

H 0.232100 2.988894 0.059321

H 3.034842 -2.805771 -1.281828

H 1.877455 -0.645060 -1.706366

H 3.494339 -2.277118 0.187970

C -3.106368 -0.036764 -0.070411

H -1.372253 1.012431 0.531882

H -1.442600 0.657583 -1.192863

O -3.816565 1.103254 -0.219117

O -3.606320 -1.118341 0.138771

H -4.761960 0.884263 -0.140778

IM2a5-2MH+

C 1.496618 -2.229246 -0.168945

C 0.770074 -0.852882 -0.161821

O 1.107441 -0.181569 -1.370982

C -0.745931 -1.058623 -0.091357

N 1.274928 0.041620 0.939838

C 0.852798 -0.273435 2.323926

H 0.944804 -2.893618 -0.838718

H 1.465543 -2.679335 0.829613

N 2.862974 -2.056170 -0.682450

H 1.046362 1.573936 0.345933

H 2.294533 -0.018257 0.899956

C -1.590729 0.213850 -0.169554

H -1.017898 -1.705838 -0.929309

H -1.000665 -1.619240 0.813657

H 1.419318 0.357943 3.012630

H -0.207335 -0.050678 2.455466

H 1.022507 -1.320298 2.601863

H 0.928838 2.051040 -1.231196

N 0.969790 2.469232 -0.294674

C 2.130956 3.399093 -0.146197

H 2.152064 3.779182 0.875446

H 3.047677 2.846352 -0.353005

H 2.036480 4.228153 -0.848004

H 0.084419 2.948522 -0.121116

H 3.107311 -2.767417 -1.363549

H 1.990405 -0.542198 -1.611176

H 3.571629 -2.086602 0.043573

C -3.079240 -0.083122 -0.109279

H -1.376727 0.907747 0.653286

H -1.403800 0.751642 -1.106069

O -3.802335 1.053838 -0.228477

O -3.570175 -1.179265 0.031660

H -4.746048 0.818348 -0.186527

TS2b5-2MH+

C 1.514355 -2.154883 -0.769095

C 0.771635 -1.024058 0.007810

O 1.268302 0.228352 -0.657542

C -0.745830 -1.096010 -0.247701

N 1.141930 -1.060202 1.379973

C 0.354095 -0.589858 2.504442

H 1.029167 -2.279036 -1.738722

H 1.414003 -3.096196 -0.217753

N 2.909895 -1.753778 -1.017955

H 1.771043 2.631131 1.270737

H 1.987896 -1.553760 1.612910

C -1.533875 0.205002 -0.062850

H -0.902988 -1.424900 -1.277952

H -1.166856 -1.881507 0.387065

H 0.864382 -0.877738 3.425810

H 0.239814 0.505804 2.530295

H -0.648263 -1.033613 2.536612

H 1.275081 1.585476 -0.005574

N 1.297966 2.624492 0.364436

C 1.988527 3.529880 -0.612374

H 1.992403 4.552411 -0.234346

H 3.011296 3.177930 -0.747227

H 1.455784 3.482142 -1.561883

H 0.335157 2.928885 0.525203

H 3.252485 -2.118407 -1.901195

H 2.171313 -0.058195 -0.957271

H 3.552415 -2.067537 -0.296273

C -3.019099 0.009997 -0.309777

H -1.434135 0.631171 0.941213

H -1.189676 0.966870 -0.771565

O -3.690039 1.176207 -0.153950

O -3.553793 -1.033268 -0.606783

H -4.633459 1.004725 -0.321792

IM2b5-2MH+

C 1.948233 -1.668636 -1.035721

C 1.028276 -0.912621 -0.039272

O 1.286211 0.531362 -0.358698

C -0.455438 -1.226991 -0.316184

N 1.424620 -1.242540 1.296789

C 0.692405 -0.712493 2.440509

H 1.525827 -1.563406 -2.037203

H 1.957313 -2.731524 -0.774322

N 3.283002 -1.043100 -1.038657

H 0.930493 3.153902 1.348125

H 2.424806 -1.127690 1.422714

C -1.455405 -0.096761 -0.054893

H -0.562205 -1.523645 -1.363270

H -0.728009 -2.107116 0.272036

H 1.200839 -1.027126 3.354317

H 0.618010 0.389811 2.462310

H -0.317752 -1.128489 2.475007

H 0.789387 1.881621 0.208803

N 0.450887 2.876767 0.488481

C 0.704162 3.863772 -0.614603

H 0.338613 4.847650 -0.320477

H 1.776677 3.903200 -0.803944

H 0.185038 3.519883 -1.508736

H -0.546972 2.820353 0.706188

H 3.705191 -1.069712 -1.961520

H 2.241795 0.500452 -0.617001

H 3.933049 -1.503238 -0.407393

C -2.891867 -0.533351 -0.281389

H -1.400948 0.287928 0.970044

H -1.271291 0.747023 -0.729855

O -3.743535 0.502090 -0.076955

O -3.252917 -1.641614 -0.599918

H -4.649681 0.180022 -0.228228

TS35-2MH+

C 1.646371 -1.954491 -0.987515

C 0.798766 -1.114205 -0.011767

O 1.313402 0.435193 -0.587299

C -0.696920 -1.153245 -0.318957

N 1.172771 -1.280306 1.294015

C 0.444521 -0.779158 2.455970

H 1.279418 -1.766744 -1.997423

H 1.469190 -3.011706 -0.755416

N 3.062125 -1.560392 -0.926397

H 1.571233 2.828379 1.365213

H 2.166477 -1.398322 1.444603

C -1.504772 0.128886 -0.088049

H -0.822058 -1.443687 -1.364887

H -1.128360 -1.969962 0.268917

H 0.923088 -1.172795 3.354032

H 0.441124 0.317657 2.520804

H -0.586510 -1.138761 2.447888

H 1.189748 1.403680 -0.033788

N 1.075103 2.728401 0.479462

C 1.607009 3.710402 -0.508247

H 1.506472 4.740185 -0.156311

H 2.662474 3.497240 -0.688288

H 1.062777 3.596593 -1.447331

H 0.098153 2.942803 0.680791

H 3.505626 -1.647804 -1.836146

H 2.268789 0.229456 -0.722387

H 3.605340 -2.135160 -0.287819

C -2.991529 -0.114354 -0.283676

H -1.378288 0.537428 0.920045

H -1.201392 0.913127 -0.788245

O -3.685935 1.038794 -0.169685

O -3.501677 -1.188648 -0.505964

H -4.630284 0.838749 -0.296790

PC5-2MH+

C 0.050580 -1.083382 1.110879

C 1.459022 -1.089573 0.532224

O -2.516171 0.114557 -0.523659

C 2.551048 -0.269265 1.149919

N 1.627329 -1.877158 -0.472234

C 2.821692 -2.081060 -1.298516

H -0.342322 -0.061810 1.026073

H 0.132214 -1.300249 2.184481

N -0.806082 -2.011486 0.392230

H -5.157895 1.742247 0.481784

H 0.731891 -2.362392 -0.695132

C 2.284510 1.249586 1.160903

H 2.645481 -0.602244 2.191912

H 3.503984 -0.469669 0.657146

H 3.641011 -2.479218 -0.695536

H 2.572900 -2.801234 -2.077021

H 3.110283 -1.130273 -1.751172

H -3.434448 0.348510 -0.193119

N -5.058863 0.732118 0.397841

C -6.127171 0.190275 -0.470568

H -7.139171 0.404285 -0.106811

H -6.024111 0.614334 -1.472803

H -6.008032 -0.893261 -0.550404

H -5.161665 0.364394 1.341952

H -1.595698 -1.504671 -0.021043

H -2.486203 0.393955 -1.447046

H -1.145951 -2.767118 0.976672

C 2.183661 1.823365 -0.238376

H 1.372971 1.509630 1.710040

H 3.100426 1.754440 1.688116

O 2.066544 3.157728 -0.223017

O 2.199628 1.154906 -1.254723

H 2.007573 3.478833 -1.140549

System: 5-M

AC5-M

C 1.908732 -1.421486 -0.583538

C 0.497061 -1.122156 -0.118037

C -0.516529 -0.746574 -1.175533

N 2.864614 -1.254899 0.502112

O 0.207324 -1.235291 1.070336

C -1.996619 -0.873636 -0.763894

C -2.528167 0.254581 0.124743

O -1.981171 0.358282 1.351021

O -3.404389 1.010200 -0.234954

H 1.864001 -2.444766 -1.006166

H 2.156131 -0.749610 -1.412376

H 2.236931 1.083256 0.609175

H -1.254754 -0.298446 1.452845

H -2.155983 -1.831104 -0.251990

H -2.617240 -0.867917 -1.661322

H 3.760610 -1.674535 0.276539

H 2.508249 -1.683703 1.352780

H -0.269678 0.282926 -1.467697

H -0.327536 -1.365346 -2.062665

N 1.527956 1.689370 0.196476

H 0.883255 1.946103 0.940236

C 2.137481 2.889082 -0.390207

H 1.357648 3.512635 -0.838758

H 2.703439 3.512933 0.319315

H 2.821079 2.591880 -1.192465

TS15-M

C -2.232806 -0.557007 0.695384

C -0.761310 -0.350521 0.210546

C 0.245835 -0.384725 1.385237

N -2.964635 -0.308125 -0.584927

O -0.529689 -1.267133 -0.756570

C 1.662580 -0.856243 0.982641

C 2.283825 -0.115022 -0.206145

O 1.709964 -0.355308 -1.386433

O 3.237692 0.635146 -0.082476

H -2.381044 -1.577005 1.049697

H -2.578855 0.168062 1.438579

H -2.288496 0.567323 -0.898768

H 0.817512 -0.888007 -1.235455

H 1.611504 -1.920018 0.728102

H 2.337954 -0.735140 1.832307

H -3.966001 -0.147561 -0.515362

H -2.727266 -1.073747 -1.224577

H 0.299730 0.585427 1.891352

H -0.133166 -1.096509 2.130682

N -0.871015 1.030316 -0.493035

H -0.197222 1.003510 -1.256514

C -0.727298 2.280693 0.269232

H 0.287323 2.435778 0.653571

H -0.978619 3.124952 -0.380505

H -1.422502 2.292921 1.115085

IM15-M

C -2.277608 -0.363183 0.676527

C -0.822254 -0.201397 0.181232

C 0.191990 -0.334585 1.343181

N -3.136418 -0.515310 -0.501349

O -0.569644 -1.275336 -0.729636

C 1.584806 -0.901204 0.976476

C 2.337237 -0.142691 -0.111769

O 1.950538 -0.400551 -1.385872

O 3.232320 0.641919 0.111348

H -2.341932 -1.282423 1.266032

H -2.548668 0.474951 1.334828

H -3.210379 0.360584 -1.011270

H 1.144406 -0.962062 -1.380707

H 1.473656 -1.947045 0.672518

H 2.215169 -0.870356 1.867850

H -4.065541 -0.842325 -0.259574

H -1.407270 -1.379129 -1.227215

H 0.310242 0.639947 1.826589

H -0.228050 -1.005995 2.100935

N -0.744479 1.044919 -0.604376

H 0.071507 1.009980 -1.208245

C -0.794447 2.327868 0.098882

H 0.029995 2.501948 0.807775

H -0.763080 3.125963 -0.647944

H -1.737828 2.431595 0.644604

TS2a5-M

C -2.264700 -0.404750 0.659429

C -0.797227 -0.243521 0.188229

C 0.193253 -0.448741 1.354943

N -3.117406 -0.471218 -0.533348

O -0.556481 -1.262139 -0.784321

C 1.606623 -0.922236 0.947187

C 2.323098 -0.084181 -0.111590

O 2.020272 -0.374807 -1.400186

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H -0.334549 1.003796 -1.442202

C -0.923997 2.314596 0.117316

H -2.007647 2.493624 0.235004

H -0.460322 2.446439 1.104486

H -0.527706 3.106390 -0.523315

IM2a5-M

C -2.260415 -0.422322 0.670667

C -0.802234 -0.227388 0.181827

C 0.202217 -0.362737 1.342010

N -3.143307 -0.503563 -0.502431

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H -0.921548 0.960326 -1.481005

C -0.989171 2.293823 0.089175

H -2.069992 2.384739 0.300455

H -0.453018 2.451069 1.029665

H -0.706398 3.112803 -0.577610

TS2b5-M

C 2.166260 -0.687305 -0.575033

C 0.726289 -0.283326 -0.165919

C -0.305789 -0.854896 -1.171204

N 3.068407 -0.535346 0.576224

O 0.469793 -0.919551 1.100431

C -1.727361 -1.115391 -0.617297

C -2.408479 0.044436 0.104833

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O -3.288971 0.718019 -0.380370

H 2.142096 -1.747592 -0.837628

H 2.482855 -0.134581 -1.467980