1. CHARMM/GAMESS-UK Paul Sherwood CLRC Daresbury Laboratory p.sherwood@dl.ac.uk

2. Overview Current implementation ¤Parallel GAMESS-UK ¤Results from Gaussian Blur / Double link atom tests ¤Plans and suggestions for QM/MM in CHARMM Link atom positions and forces Boundary charge corrections CHARMM performance on DL Beowulf clusters ¤Pentium/Ethernet ¤Alpha/Quadrics Advert for QUASI workshop (Mülheim) Sept 25-27 2000

3. CHARMM/GAMESS-UK Interface Implemented with help from Bernie Brooks, Eric Billings QM/MM model closely follows CHARMM/GAMESS(US) Gaussian Blur implemented ¤based on generic auxilliary charge density expansion - taken from Dunlap fitted DFT scheme. ¤includes gradients ¤could be generalised to coulomb interactions based on non-spherical charge densities ¤Incorporated into parallel CHARMM, based on a single distributed QM calculation

4. GAMESS-UK Parallel Implementation ¤Replicated data scheme store P, F, S etc on every node minimal communications (load balancing, global sum) up to ca. 2000 basis functions ¤Message-passing version (MPI, TCGMSG) SCF and DFT Suitable for < 32 processors ¤Global Array version: Parallel functionality –SCF, DFT, MP2, SCF Hessian Parallel algorithms –GAs for in-core storage of transformed integrals (to vvoo) and MP2 amplitudes –parallel linear algebra (PEIGS, DIIS, MXM etc) –GA-mapped ATMOL file system

5. QM region (69 Atoms) is modelled by SCF 6-31G calculation (401 GTOs), total system size for the classical calculation is 16,659 atoms. The MM calculation was performed using all non-bonded interactions (i.e. without a pairlist), and the QM/MM interaction was cut off at 15 angstroms using a neutral group scheme (leading to the inclusion in the QM calculation of 1507 classical centres). Number of Nodes Thrombin QM/MM Benchmark

6. Creation of neutral embedding site (i) Neutral charge groups Deletion according to force-field neutral charge-group definitions Total charge conserved, poor dipole moments C N C C O HR N H C O R HH

7. Creation of neutral embedding site (iii) Double link atoms Suggestion from Brooks (NIH) for general deletion (not on a force-field neutral charge-group boundary) All fragments are common chemical entities, automatic charge assignment is possible. C N C C O H R N H C O R H H H H

8. Creation of neutral embedding site Double Link Atoms Conventional QM/MM schemes ¤Break into H 3 C and CH 3 Neutral fragments (in this simple case) Non-zero individual dipoles ¤Replace QM CH 3 with some form of terminated group (L-CH 3 ) Finite total dipole moment Often further adjustment to MM charges is required (may create additional charge and dipole errors). Double link atom Dipole generally well approximated by superposition of bonds C C H H H H H H C C H H H H H H H MM QM C C H H H H H H H H

9. Boundary adjustments ¤Some of the classical centres will lie close to link atom (L) ¤Artefacts can result if charge at the M 1 centre is included in Hamiltonian, many adjustment schemes have been suggested Adjustments to polarising field can be made independently from specification of MM…MM interactions Similar adjustments may are needed if M 1 is classified as a boundary atom, depending on M 1 treatment. M2M2 M1M1 Q1Q1 Q2Q2 Q2Q2 M2M2 M3M3 Q3Q3 L

10. Boundary Adjustments (i) Selective deletion of 1e integrals ¤L1: Delete integrals for which basis functions i or j are sited on the link atom L found to be effective for semi-empirical wavefunctions difference in potential acting on nearby basis functions causes unphysical polarisation for ab-initio QM models ¤L3: Delete integrals for which basis functions i and j are cited on the link atom and q A is the neighbouring MM atom (M 1 ) less consistent results observed in practice † † Classification from Antes and Thiel, in Combined Quantum Mechanical and Molecular Mechanical Methods, J. Gao and M. Thompson, eds. ACS Symp. Ser., Washington DC, 1998.

11. Boundary Adjustments (ii) Deletion of first neutral charge group ¤Thiel L2, CHARMM EXGR Option ¤Exclude charges on all atoms in the neutral group containing M 1 Maintains correct MM charge –leading error is the missing dipole moment of the first charge group Generally reliable –free from artefacts arising from close contacts Limitations –only applicable in neutral group case (e.g. AMBER, CHARMM) –neutral groups are highly forcefield dependent differ between MSI and Academic charmm –problematic if a charge group needs to be split Application –biomolecular systems

12. Boundary adjustments (iii) Charge shift ¤Delete charge on M 1 ¤Add an equal fraction of q(M 1 ) to all atoms M 2 ¤Add correcting dipole to M 2 sites (implemented as a pair of charges) charge and dipole of classical system preserved Leading sources of residual error is that Q---L dipole moment is not equivalent to Q------M M2M2 M1M1 Q1Q1 Q2Q2 Q2Q2 M2M2 M3M3 Q3Q3 L

13. Boundary adjustments (iv) Gaussian Blur ¤Delocalise point charge using Gaussian shape function Large Gaussian width : electrostatic coupling disappears Narrow Gaussian width : recover point charge behaviour Intermediate values –short range interactions are attenuated –long range electrostatics are preserved ¤Importance of balance - apply to entire MM system or to first neutral group ¤Particularly valuable for double-link atom scheme where MM link atom charge lies within QM molecular envelope

14. Gaussian Blur: QM/MM Ethane Aggregate dipole moment, with MM atoms broadened ¤Large Gaussian width dipole converges to that of the QM methane ( 0 ) ¤Small Gaussian width point charges polarise the QM region, away from the C-H bond MM QM C C H H H H H H H H Compare with dipole of MM methyl group (0.18)

15. QM/MM coupling - Proton Affinity Tests Simplified alcohol test set based on [1] ¤AMBER charge model ¤QM region is small (HOCH 3 in all cases) ¤Include systems with 1, 2 and 3 link atoms, Ethanol, i-Propanol, t-Butanol ¤Fixed geometries (from 3-21G QM optimisations) ¤Compare Pure QM L2 (delete first charge group) Shift (move charge from first atom to neighbours, add dipole. Double link atom + Gaussian Blur H C CH 3 O H C O H H C O H H [1] I. Antes and W. Thiel, in “Hybrid Quantum Mechanical and Molecular Mechanical Methods” J. Gao (ed.) ACS Symp.Ser. 712, ACS, Washington, DC, 1998.

16. Computed Proton Affinities

17. Possible Developments Planned in collaboration with NIH ¤task-farmed parallel implementation (based on multiple MPI communicators) for use on high latency parallel machines (Beowulfs) ¤Automated setup of double link atoms Suggestions for QM/MM couplings ¤Handling of link atoms - inclusion of chain run derivatives to remove link atoms from dynamics. ¤Shifted charge at boundaries as an alternative to EXGR - especially where large neutral groups are involved.

18. Initial placement ¤Usually on terminated bond Unconstrained ¤Additional degrees of freedom present in geometry optimisation and MD e.g. CHARMM, QUEST Constrained ¤Need to take into account forces on link atoms, shared internal coordinate definitions (IMOMM) chain-rule differentiation (QM/Pot, ChemShell) Positioning of link atoms

19. QUASI Workshop Modelling Catalysis - Quantum Simulations in Industry September 27-27, MPI Mülheim Plenary speakers ¤M. Karplus (Strasbourg) - biocatalysis ¤L.G.M Pettersson (Stockholm) - solid-state and surfaces ¤J. Sauer (Berlin) - zeolites ¤M. T. Reetz (MPI Mülheim) - experimental perspective QUASI Consortium speakers ¤C.R.A. Catlow, P. Sherwood, W. Thiel ¤Industrial perspective A. Schäfer (BASF), S. Rogers (ICI), M. Sjovoll (Hydro) ¤M. F. Guest (HPC) Posters and Hands-on session www.mpi-muelheim.de/QUASI/workshop

20. QUASI Workshop - Mülheim Sept 25-27 2000 Richard Catlow (Royal Institution, London) QM/MM Techniques for Modelling Bulk and Surface Properties of Oxide Materials Martyn Guest (Daresbury Laboratory, CLRC) Molecular Modelling on High-End and Commodity-Type Computers: Status and Perspectives  Martin Karplus (Université de Strasbourg) How Enzymes Work: Activation Energy and Dynamics  Lars Pettersson (University of Stockholm) To be announced  Manfred Reetz (MPI für Kohlenforschung, Mülheim) Evolution in the Test Tube as a Means to Create Enantioselective Enzymes for Organic Chemistry Steve Rogers (ICI, Teesside) QM/MM Studies of Methanol Synthesis  Joachim Sauer (Humboldt-Universität Berlin) QMPOT: A Powerful Tool for Modelling Catalysis by Zeolites  Ansgar Schäfer (BASF, Ludwigshafen) Large-scale QM/MM Calculations on Enzymes  Helmut Schwarz (Technische Universität Berlin) Mechanistic Studies on the Platinum Mediated HCN Synthesis from Methane and Ammonia  Paul Sherwood (Daresbury Laboratory, CLRC) Implementation of the QM/MM Methodology within QUASI - a General Purpose Approach.  Merethe Sjovoll (Norsk Hydro, Porsgrunn) Catalytic Decomposition of Nitrogen Oxides by Transition Metal-Exchanged Zeolites  Walter Thiel (MPI für Kohlenforschung, Mülheim) QM/MM Studies on Enzymes: Methods and Applications