Supporting Information Structural Characterization of Drug-like ...
Supporting Information
Structural Characterization of Drug-like Compounds by Ion Mobility Mass Spectrometry: Comparison of Theoretical and Experimentally Derived Nitrogen Collision Cross-sections Iain Campuzano1, Matthew F. Bush2, Carol V. Robinson3, Claire Beaumont4, Keith Richardson5, Hyungjun Kim6 and Hugh I. Kim7 1
Amgen Inc. Department of Molecular Structure, Thousand Oaks, CA, 91320, USA.
2
Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
3
Department of Chemistry, Physical and Theoretical Laboratory, University of Oxford,
Oxford, OX1 3QZ, UK. 4
PTS DMPK, GlaxoSmithKline, Ware, Herts, SG8 7SW, UK.
5
Waters Corporation, MS Technologies Centre, Manchester, M22 5PP, UK.
6
Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
7
Pohang University of Science and Technology, Pohang, Korea.
Corresponding authors: [email protected] and [email protected]
Figure S1. Small molecule calibration mix N2 drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms). IM measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.1 Torr N2.
Figure S2. Small molecule calibration mix He drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms). IM measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.7 Torr He.
Figure S3.
Tetra-alkylammonium mix N2 drift-tube measurements plotted as the
reciprocal of the drift-voltage (V) versus the measured drift-time (ms). IM measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.1 Torr N2.
Figure S4.
Tetra-alkylammonium mix He drift-tube measurements plotted as the
reciprocal of the drift-voltage (V) versus the measured drift-time (ms). IM measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.7 Torr He.
Table S1. Drift-tube derived ΩN2 and ΩHe values for the tetra-alkylammonium mix. The letter n denotes the length of the alkyl chain; n=1 methyl, n=2 ethyl, n=3 propyl, n=4 butyl, n=5 pentyl. n=6 hexyl, n=7 heptyl and n=8 octyl. Values in parentheses represent the standard deviation, in percentage, of the IM measurement.
Figure S5. C60, C70 and PAH radical cation mix N2 drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms).
IM
measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.1 Torr N2.
.
Figure S6. C60, C70 and PAH radical cation mix He drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms).
IM
measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.7 Torr He.
Figure S7. Betamethasone (and dimer), dexamethasone (and dimer), choline (and HCl salt dimer) and acetylcholine (and HCl salt dimer) N2 drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms).
IM
measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.1 Torr N2.
Figure S8.
Betamethasone, dexamethasone, choline and acetylcholine He drift-tube
measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drifttime (ms). IM measurements were made at 10 different drift voltages, ranging from 60– 200 V in 2.7 Torr He.
Figure S9. Acetaminophen protonation sites, B3LYP/6-31G++(d,p) calculated energies (Hartree) and relative energy level differences (kcal mol-1). Trajectory method Ω values (both N2 and He) are calculated for the two most stable structures 1,2.
Table S2. Drift-tube (DT; ΩN2 and ΩHe) and optimized trajectory method (TJ) derived (ΩN2 and ΩHe) values.
Numbers in parentheses indicate the standard deviation, in
percentage of the measurement.
The symbol * denotes only a single experiment
comprising of ten drift-time versus reciprocal drift-voltage measurement were carried out. The symbol † denotes that dimeric structures were not created or optimized by DFT, therefore, no trajectory method calculations were performed. The symbol ‡ denotes that theoretical Ω value was an average of two lowest energy structures. Trajectory method standard deviations are based on using an impact factor (imp) of 1000.
Figure S10. T-wave separator calibration using the small molecule calibration mix. A power curve (y=axn) was fit to the data.
Data acquired at a T-wave velocity and
amplitude of 450 m/s (1), 475 m/s (2) and 500 m/s (3) and 40 V, respectively.
Figure S11. Anthracene and phenanthrene radical cation structures. Also annotated are the theoretical trajectory method (TJ) ΩN2, ΩHe values and drift-tube ΩN2, ΩHe values.
Figure S12. Betamethasone and dexamethasone protonation sites, B3LYP/6-31G++(d,p) calculated zero-point energies (Hartree) and relative energy level differences (kcal mol-1). The symbol * denotes the only chiral centre with a different configuration.
Figure S13.
Betamethasone electrostatic surface potential partial atomic charge
distribution calculated using B3LYP/6-31G++(d,p) with the keyword pop=(mk,dipole).
Figure S14.
Dexamethasone electrostatic surface potential partial atomic charge
distribution calculated using B3LYP/6-31G++(d,p) with the keyword pop=(mk,dipole).
Notes on the Trajectory Method Note that within the original He trajectory method MOBCAL code 3, the atom fluorine (F) is not accounted for. Typically it would be replaced by iron (Fe) which possess the same Lennard-Jones values are silicon (Si); ϵ 1.35 meV and σ 3.5 Å. Within the MOBCAL code (lines 596, 595 and 2762, 2761 respectively, for atom hydrogen) the atomic energy (ϵ) and van der Waals distance (σ) values are represented by the terms eolj and rolj respectively. The original N2 trajectory method code
4
was written and tuned to operate optimally at
473 K. This temperature value was reduced to 301K in the source code; line 214. All mfj files were computed containing partial atomic charge, therefore, utilizing the term calc in line 5 of the mfj file. The optimized N2 and He trajectory method source code can be supplied upon request.
(1) Alex, A.; Harvey, S.; Parsons, T.; Pullen, F. S.; Wright, P.; Riley, J. A. Rapid Commun. Mass Spectrom. 2009, 23, 2619. (2) Wright, P.; Alex, A.; Nyaruwata, T.; Parsons, T.; Pullen, F. Rapid Commun. Mass Spectrom. 2010, 24, 1025. (3) Mesleh, M. F. H., J. M. Shvartsburg, A. A. Schatz, G. C. Jarrold, M. F. Journal of Physical Chemistry 1996, 100, 16082. (4) Kim, H.; Kim, H. I.; Johnson, P. V.; Beegle, L. W.; Beauchamp, J. L.; Goddard, W. A.; Kanik, I. Anal. Chem. 2008, 80, 1928.
Structural Characterization of Drug-like Compounds by Ion Mobility Mass Spectrometry: Comparison of Theoretical and Experimentally Derived Nitrogen Collision Cross-sections Iain Campuzano1, Matthew F. Bush2, Carol V. Robinson3, Claire Beaumont4, Keith Richardson5, Hyungjun Kim6 and Hugh I. Kim7 1
Amgen Inc. Department of Molecular Structure, Thousand Oaks, CA, 91320, USA.
2
Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
3
Department of Chemistry, Physical and Theoretical Laboratory, University of Oxford,
Oxford, OX1 3QZ, UK. 4
PTS DMPK, GlaxoSmithKline, Ware, Herts, SG8 7SW, UK.
5
Waters Corporation, MS Technologies Centre, Manchester, M22 5PP, UK.
6
Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
7
Pohang University of Science and Technology, Pohang, Korea.
Corresponding authors: [email protected] and [email protected]
Figure S1. Small molecule calibration mix N2 drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms). IM measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.1 Torr N2.
Figure S2. Small molecule calibration mix He drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms). IM measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.7 Torr He.
Figure S3.
Tetra-alkylammonium mix N2 drift-tube measurements plotted as the
reciprocal of the drift-voltage (V) versus the measured drift-time (ms). IM measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.1 Torr N2.
Figure S4.
Tetra-alkylammonium mix He drift-tube measurements plotted as the
reciprocal of the drift-voltage (V) versus the measured drift-time (ms). IM measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.7 Torr He.
Table S1. Drift-tube derived ΩN2 and ΩHe values for the tetra-alkylammonium mix. The letter n denotes the length of the alkyl chain; n=1 methyl, n=2 ethyl, n=3 propyl, n=4 butyl, n=5 pentyl. n=6 hexyl, n=7 heptyl and n=8 octyl. Values in parentheses represent the standard deviation, in percentage, of the IM measurement.
Figure S5. C60, C70 and PAH radical cation mix N2 drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms).
IM
measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.1 Torr N2.
.
Figure S6. C60, C70 and PAH radical cation mix He drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms).
IM
measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.7 Torr He.
Figure S7. Betamethasone (and dimer), dexamethasone (and dimer), choline (and HCl salt dimer) and acetylcholine (and HCl salt dimer) N2 drift-tube measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drift-time (ms).
IM
measurements were made at 10 different drift voltages, ranging from 60–200 V in 2.1 Torr N2.
Figure S8.
Betamethasone, dexamethasone, choline and acetylcholine He drift-tube
measurements plotted as the reciprocal of the drift-voltage (V) versus the measured drifttime (ms). IM measurements were made at 10 different drift voltages, ranging from 60– 200 V in 2.7 Torr He.
Figure S9. Acetaminophen protonation sites, B3LYP/6-31G++(d,p) calculated energies (Hartree) and relative energy level differences (kcal mol-1). Trajectory method Ω values (both N2 and He) are calculated for the two most stable structures 1,2.
Table S2. Drift-tube (DT; ΩN2 and ΩHe) and optimized trajectory method (TJ) derived (ΩN2 and ΩHe) values.
Numbers in parentheses indicate the standard deviation, in
percentage of the measurement.
The symbol * denotes only a single experiment
comprising of ten drift-time versus reciprocal drift-voltage measurement were carried out. The symbol † denotes that dimeric structures were not created or optimized by DFT, therefore, no trajectory method calculations were performed. The symbol ‡ denotes that theoretical Ω value was an average of two lowest energy structures. Trajectory method standard deviations are based on using an impact factor (imp) of 1000.
Figure S10. T-wave separator calibration using the small molecule calibration mix. A power curve (y=axn) was fit to the data.
Data acquired at a T-wave velocity and
amplitude of 450 m/s (1), 475 m/s (2) and 500 m/s (3) and 40 V, respectively.
Figure S11. Anthracene and phenanthrene radical cation structures. Also annotated are the theoretical trajectory method (TJ) ΩN2, ΩHe values and drift-tube ΩN2, ΩHe values.
Figure S12. Betamethasone and dexamethasone protonation sites, B3LYP/6-31G++(d,p) calculated zero-point energies (Hartree) and relative energy level differences (kcal mol-1). The symbol * denotes the only chiral centre with a different configuration.
Figure S13.
Betamethasone electrostatic surface potential partial atomic charge
distribution calculated using B3LYP/6-31G++(d,p) with the keyword pop=(mk,dipole).
Figure S14.
Dexamethasone electrostatic surface potential partial atomic charge
distribution calculated using B3LYP/6-31G++(d,p) with the keyword pop=(mk,dipole).
Notes on the Trajectory Method Note that within the original He trajectory method MOBCAL code 3, the atom fluorine (F) is not accounted for. Typically it would be replaced by iron (Fe) which possess the same Lennard-Jones values are silicon (Si); ϵ 1.35 meV and σ 3.5 Å. Within the MOBCAL code (lines 596, 595 and 2762, 2761 respectively, for atom hydrogen) the atomic energy (ϵ) and van der Waals distance (σ) values are represented by the terms eolj and rolj respectively. The original N2 trajectory method code
4
was written and tuned to operate optimally at
473 K. This temperature value was reduced to 301K in the source code; line 214. All mfj files were computed containing partial atomic charge, therefore, utilizing the term calc in line 5 of the mfj file. The optimized N2 and He trajectory method source code can be supplied upon request.
(1) Alex, A.; Harvey, S.; Parsons, T.; Pullen, F. S.; Wright, P.; Riley, J. A. Rapid Commun. Mass Spectrom. 2009, 23, 2619. (2) Wright, P.; Alex, A.; Nyaruwata, T.; Parsons, T.; Pullen, F. Rapid Commun. Mass Spectrom. 2010, 24, 1025. (3) Mesleh, M. F. H., J. M. Shvartsburg, A. A. Schatz, G. C. Jarrold, M. F. Journal of Physical Chemistry 1996, 100, 16082. (4) Kim, H.; Kim, H. I.; Johnson, P. V.; Beegle, L. W.; Beauchamp, J. L.; Goddard, W. A.; Kanik, I. Anal. Chem. 2008, 80, 1928.
