Ultrafast Shape Recognition for Similarity Search in Molecular Databases

Pedro J. Ballester1 & W. Graham Richards1

1Physical & Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK.

SUMMARY:

Molecular databases are routinely screened for compounds that most closely resemble a molecule of known biological activity to provide novel drug leads. It is widely believed that 3D molecular shape is the most discriminating pattern for biological activity, as it is directly related to the steep repulsive part of the interaction potential between the drug-like molecule and its macromolecular target. However, efficient comparison of molecular shape is currently a challenge. Here we show that a new approach [1][2] based on moments of distance distributions is able to recognise molecular shape at least three orders of magnitude faster than current methodologies.  Such an ultrafast method permits the identification of similarly shaped compounds within the largest molecular databases. In addition, the problematic requirement of aligning molecules for comparison is circumvented, as the proposed distributions are independent of molecular orientation.

KEYWORDS: 

Molecular Shape; Similarity Search; Pattern Recognition; Data Explosion; Virtual Screening.

REFERENCES: 

[1] Ballester, P.J. and Richards, W.G.: "Ultrafast Shape Recognition to Search Compound Databases for Similar Molecular Shapes", Journal of Computational Chemistry (In Press)

[2] Ballester, P.J. and Richards, W.G.: "Ultrafast Shape Recognition for Similarity Search in Molecular Databases", Proceedings of the Royal Society A (In Press)

 

 

Class A b-lactamases: a QM/MM study of their mechanism of resistance to antibiotics.

 

Juliette J. Pradon, Dr. Jeremy N. Harvey and Dr. Adrian J. Mulholland.

 

School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.

 

b-lactam compounds work by irreversibly inhibiting penicillin-binding proteins, which are enzymes responsible for the synthesis and repair of peptidoglycan, a major structural component of bacterial cell walls. The production of b-lactamase enzymes by many pathogenic bacteria makes them resistant to both naturally occurring and synthetically developed b-lactam compounds, such as penicillins, cephalosporins and carbapenems. These enzymes are able to hydrolyse the amide bond in the b-lactam ring. This represents a growing problem in current primary care medicine.

For class A b-lactamases, which are the most prevalent form in pathological strains, the overall catalytic mechanism is a two-step process: the enzyme is rapidly acylated at residue Ser70 by the b-lactam; the serine ester intermediate is then hydrolysed, leading to release of the cleaved, inactive antibiotic. Whilst the process of deacylation is widely accepted, there is no such consensus on the acylation step.

The acylation mechanism of a class A TEM-1 b-lactamase by the anionic form of benzylpenicillin was studied with the combined Quantum Mechanics/Molecular Mechanics (QM/MM) methodology.

 

 

 

 

 

Modelling reactions of drugs in human cytochrome P450 enzymes

 

Richard Lonsdale, Dr. Jeremy Harvey and Dr. Adrian Mulholland

 

School of Chemistry, University of Bristol, Bristol, BS8 1TS

 

Cytochrome P450 (CYP) is an important metalloenzyme found in plants, animals and bacteria. It activates molecular oxygen and catalyzes stereoselective and regioselective oxygen insertion reactions with a wide variety of organic compounds. These enzymes are of particular interest in the field of drug metabolism, because they play an important role in the disposition of drugs and in their pharmacological and toxicological effects. A key aim is the prediction of selectivity of reactions of drugs with different P450 isozymes. Combined quantum mechanics/molecular mechanics methods now allow reactions in P450 enzymes to be modelled, and provide a promising approach to analysing determinants of selectivity in drug metabolism.

CYP 2C9 is one of the major drug metabolizing isoforms of the enzyme. It contributes to the metabolism of around 16% of drugs that are in current clinical use. The large and highly flexible substrate binding cavity enables it to bind multiple substrate molecules. This may give rise to adverse drug reactions. The widely used anticoagulant drug S-warfarin undergoes stereoselective hydroxylation by CYP 2C9 to the biologically inactive S-7-hydroxywarfarin. A crystal structure exists of CYP 2C9 complexed with S-warfarin which places the warfarin molecule 10 Å from the active oxidizing species. We have investigated the mobility and conformational behaviour of warfarin in CYP by molecular dynamics simulations. This has provided a basis for modelling the oxygen insertion reaction of S-warfarin in CYP 2C9. The results provide detailed insight into the reaction in the enzyme active site.

            In the case of allylic substrates, regioselectivity is an important consideration.  For example, the oxidation of cyclohexene by the bacterial P450cam from pseudomonas putida results in both C=C bond epoxidation and allylic hydroxylation products in approximately equal amounts.  In contrast, oxidation of propene gives exclusively epoxidation-type products.  Application of QM/MM methodology to this problem yields relative barriers for bond-activation in these processes which are consistent with experimental findings.

 

References

C. M. Bathelt, L. Ridder, A. J. Mulholland and J. N. Harvey, Org. Biomol. Chem., 2004, 2, 2998-3005

C. M. Bathelt, J. Zurek, A. J. Mulholland and J. N. Harvey, J. Am. Chem. Soc., 2005, 127, 12900-12908.

A. J. Mulholland, Drug Discovery Today, 2005, 10, 1393-1402

 

 

 

Modelling the mechanism of citrate synthase: evidence for arginine acting as acid

 

Marc van der Kamp, Adrian Mulholland

 

Centre for Computational Chemistry, School of Chemistry, University of Bristol, UK.

Marc.vanderKamp@bristol.ac.uk

 

Citrate synthase catalyses the first step in the citric acid cycle: the conversion of oxaloacetate to citrate. The first reaction in this conversion is the Claisen condensation of acetyl-CoA with the carbonyl of oxaloacetate. This reaction comprises two steps: proton abstraction from acetyl-CoA to form an enolate (enolization, previously thought to be rate limiting1) and the subsequent nucleophilic attack of the enolate on the carbonyl carbon of oxaloacetate (condensation). The overall mechanism of this important enzyme remains uncertain.

We have identified a new mechanism for the reaction, in calculations which have also highlighted important shortcomings in standard modelling methods. Potential energy profiles both reaction steps were obtained using QM/MM modelling at several QM levels, including high-level ab initio approaches. Higher level results (e.g. SCS-MP2) indicate the enolate is a real minimum, about 3 kcal/mol more stable than the transition state. QM/MM modelling of the next step of the reaction (nucleophilic attack on the oxaloacetate carbonyl carbon), shows some novel and interesting mechanistic features. This step is concerted with an unusual proton transfer from an arginine residue to the carbonyl oxygen. The barrier is higher than for the enolization reaction, indicating that condensation is rate limiting. For both reaction steps, the standard B3LYP functional fails to describe the reaction correctly. The results have important general implications for modelling enzyme reactions.

Analysis of stabilization by the enzyme and key individual residues along the full profile was performed. This indicates that the enzyme primarily stabilizes between the transition states of the condensation reaction, providing more evidence that this second step is likely to be rate limiting.

 

1. Lenz, H. et al., Eur. J. Biochem. (1971), 24, 207-15





 

 

 

 

 

Understanding the Extracellular Matrix of Microbial Biofilms: Molecular Modelling the Structure and Dynamics of Alginate in the Condensed Phase

Hoda Abdel-Aal Bettley and Richard A. Bryce*

 

School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PL, UK

 

Alginate copolymers are a key component of the extracellular polymeric substances (EPS) matrix of microorganisms such as P. aeruginosa. Alginate helical chains comprise alternating blocks of a-(1®4)-linked L-guluronate and b-(1®4)-linked D-mannuronate. To understand the microscopic behaviour and interactions of these flexible acidic sugars within the EPS matrix, a suitable molecular-level model is required. To this end, we derive a molecular mechanical force field for the two uronic acids, with validation against available experimental data. We subsequently explore alginate models of increasing complexity, from disaccharides to single- and double-stranded oligomer helices, employing the techniques of molecular dynamics and replica-exchange molecular dynamics. The condensed phase behaviour of these systems is discussed, including the role of counterions and the implications for interaction with other constituents of the EPS matrix.

 

 

 

 

 

 

Transition Metals in Metalloproteins and Pharmaceuticals:  How to get QM Accuracy at MM Prices

 

Robert J Deeth


Inorganic Computational Chemistry Group,  University of Warwick

r.j.deeth@warwick.ac.uk

 

Abstract:

Transition metal (TM) centres play crucial roles in many metalloproteins and are finding increasing applications in pharmaceuticals.  However, despite their growing significance in biology and medicine, computational approaches to TM systems remain underdeveloped.  Their structural and electronic complexity apparently precludes a general molecular mechanics (MM) approach while quantum mechanics (QM) is expensive.  Consequently, simulations of TM-containing molecules tend to be restricted to small systems which are tractable for QM or tend to require more-or-less crude assumptions to facilitate classical modelling.

The central feature which distinguishes TMs from the lighter ‘organic’ elements is the crucial role played by the d electrons.  The d electrons are structurally end electronically non-innocent and their influence must be explicitly or implicitly incorporated in any theoretical treatment.  One way of including d electron effects is via ligand field theory (LFT) which is empirical, and thus computationally efficient, but accurate and flexible enough to enable TM atoms to be placed on the same footing as any other atom type in the MM force field.  Consequently, by augmenting conventional MM with an explicit calculation of d electron effects via LFT, we arrive at ligand field molecular mechanics (LFMM) which is capable of delivering the accuracy of full QM but several orders of magnitude faster.  The LFMM offers the potential for the accurate modelling of electronically challenging metals centres like Cu(II), provides a common energy reference for treating multiple spin states in Ni(II) and Fe(II) systems and is efficient enough to be applied to entire protein systems.

 

 

Molecular dynamics study of chemically engineered green fluorescent protein mutants: comparison of intramolecular fluorescence resonance energy transfer efficiency

 

Felicity L. Mitchell1, Filipp Frank2, Gabriel E. Marks1, Kenneth T. Douglas1, Miho Suzuki3, Richard A. Bryce1*

 

1School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK. 2 Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany. 3Functional Materials Science, Graduate school of Science and Engineering, Saitama University, Shimo-okubo, Saitama, 338-8570, Japan

 

Due to its unusual spectroscopic properties, green fluorescent protein has become a useful tool in molecular genetics, biochemistry and cell biology. Here, we computationally explore the behaviour of two green fluorescent protein constructs, designed as bioprobes for enzymatic triggering using intramolecular fluorescence resonance energy transfer (FRET). These constructs differ in the location of the intramolecular FRET partner, an attached chemical chromophore (either at a N-terminal or C-terminal site). We apply the temperature replica exchange molecular dynamics method to the two flexible constructs in conjunction with a generalised Born implicit solvent model, permitting efficient sampling of protein/chromophore phase space. The calculated efficiency of FRET was derived from the inter-chromophore distance and orientation factor k2. In agreement with experiment, the construct with the C-terminally attached dye was found to have significantly higher energy transfer efficiency than observed for the N-terminal construct. The molecular basis for this observation is discussed.

 

 

The influence of MD simulations on ligand-protein docking

 

Emi Psachoulia, Philip C. Biggin

 

Dept. of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, U.K.
 

Docking techniques are widely used to find plausible conformations of a ligand and its receptor. Current docking programs typically allow flexible ligands and limited protein flexibility typically just sidechain rotamers. Molecular dynamics (MD) has been suggested as a useful complementary tool for use in conjunction with molecular docking programs [1]. However, the influence of MD on docking has not yet been systematically examined.

The aim of this project was to examine the influence of molecular dynamics on the docking using a subset of CCDC/Astex test set previously used to validate GOLD [2].

11 protein-ligand complexes from different classes of protein, i.e. hydrolase, kinase, lyase, etc., were chosen and 10 ns MD protein only simulations were run with Gromacs. Protein stability was accessed by Cα-RMSD calculations of the whole protein and of the residues at the binding pocket. Snapshots were taken from a 5 ns portion of the trajectory, where the proteins were stable, and ligands were docked back to these frames.

The results and relevance to future drug-design approaches will be discussed.

 

1. Alonso H, Bliznyuk AA,  Gready JE. Combining docking and molecular

  dynamic simulations in drug design. Med. Res. Rev. 2006; 26: 531-568.

 2. Nissink JW, Murray C, Hartshorn M, Verdonk ML, Cole JC, Taylor R. A new test set for validating predictions of protein-ligand interaction. Proteins. 2002; 49: 457-471.

 

Phosphorilation of p47phox:

In silico Phosphorylation of the superSH3 domain of p47phox. 

 

Bruno Pagano$, Flavia Autore#^, Katrin Rittinger*  and Franca Fraternali^

 

$Dipartimento di Scienze Farmaceutiche, Universita’ di Salerno, via Ponte Don Melillo 84084, Fisciano, Salerno, Italy.

#Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, Complesso Universitario Monte Sant’Angelo, via Cynthia, 80126, Naples, Italy.

*Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA, London, U.K

^King’s College Bioinformatics Unit, Randall Division of Cell and Molecular Biophysics, New Hunt's House, SE1 1UL, London, U.K.

 

NADPH oxidase is an enzymatic complex that catalyzes the reduction of oxygen to a superoxide anion (O2-) as response against microbial infection. The multiple complex comprises a heterodimeric membrane-bound flavocytochrome, b558 (gp91phox and p22phox), and four cytosolic regulatory subunits [1]. A crucial step for the assembly and activation of enzyme is the phosphorylation of one of the cytosolic subunits, p47phox, of specific serines [2]. The p47phox subunit contains a PX domain, tandem SH3 domains (superSH3 domain), a polybasic region/autoinhibitory region (PBR/AIR) and a proline-rich C-terminus region. In the inactive state the SH3 domains interact thought intramolecular interactions with the PBR/AIR region, resulting in the autoinhibited form. Phosphorylation of p47phox induces conformational changes that lead to intramolecular interactions rearrangements and allow the SH3 domains to gain interaction with the p22phox membrane subunit of the complex. Phosphorylation of Ser303 Ser304 and Ser328 was suggested to be required for the NADPH oxidase activation [3]. Starting from the crystal structure [4] we investigated by Molecular Dynamics (MD) simulations and Essential Dynamics (ED) sampling the effect of these phosphorylated sites on the dynamical behaviour of the superSH3 domain.  Molecular dynamic simulations of the phosphorylated form compared to auto-inhibited form have demonstrated that conformational changes phosphorylation-induced lead to the loss of about 70% of the interactions between SH3 domains and the PBR/AIR region. Principal components analysis of the simulation reveals that the first 2 eigenvectors account for 56% of the global motion. Essential Dynamic was employed to encourage the protein to move towards the first and the second eigenvector to explore a larger region of space than it would in free MD. After this sampling most of the residues interacting with p22phox become exposed, suggesting that phosphorylation induces a conformational change leading to the accessibility of these residues for a competitive binding.

 

[1]        B. M. Babior, Blood (1999) 93:1464.

[2]        H. Sumimoto, Y. Kage, H. Nunoi, H. Sasaki, T. Nose, Y. Fukumaki, M. Ohno, S. Minakami, and K. Takeshige, Proc Natl Acad Sci U S A (1994) 91:5345.

[3]        T. Ago, H. Nunoi, T. Ito, and H. Sumimoto, J Biol Chem (1999) 274:33644.

[4]        Y. Groemping, K. Lapouge, S. J. Smerdon, and K. Rittinger, Cell (2003) 113:343.

 

 

 

 

 

Modelling the Mechanism of Chitinase B

 

Heather Rowlands, Adrian Mulholland

 

University of Bristol

Heather.rowlands@bristol.ac.uk

 

Chitinase is an important enzyme from the glycosyl hydrolase family of enzymes.  Found in a diverse and numerous collection of organisms, it catalyses the break down of chitin, releasing dimers and trimers in a progressive manner.  Due to its presence in such a wide range of organisms from yeast and bacteria to insects and crustaceans, it is a good target for inhibitors in the form of fungicides, insecticides and anti-malarials.  An enzyme with chitinase activity has recently been found in humans and has been suggested to play a role in defence against chitin containing pathogens.

 

Better understanding of the mechanism of this enzyme could help in the design of novel inhibitors.  A mechanism for chitinase B has been proposed from structural and mutational studies is, in some ways, similar to that of lysozyme and other amylases.  The nucleophilic attack in particular differs from other glycosyl hydrolases in that the N-acetyl group of the sugar ring itself is the nucleophile, compared with lysozyme where the nucleophile is an aspartate side chain.  Quantum Mechanics/Molecular Mechanics (QM/MM) techniques have been employed in this study to investigate the reaction profile of each step in the mechanism.

 

D. M. F. van Aalten, D. Komander, B. Synstad, S. Gåseidnes, M. G. Peter and V. G. H. Eijsink (2001). PNAS, 98(16) 8979-8984.

 

F. Fusetti, H. von Moeller, D. Houston, H. J. Rozeboom, B. W. Dijkstra, R. G. Boot, J. M. F. G. Aerts and D. M. F. van Aalten (2002). J. Biol. Chem., 277(28) 25537-25544

 

Design, synthesis and evaluation of dual acting estrogen receptor conjugates

Design, synthesis and evaluation of dual acting estrogen receptor conjugates

 

N.O. Keely, M.J. Meegan

 

School of Pharmacy & Pharmaceutical Sciences, Panoz Institute, Trinity College, Dublin

 

            In this study, specific structural requirements of drug-like molecules for optimum estrogen receptor binding are examined. The design, synthesis and binding of ligands to both the steroid and non-steroid binding sites in the estrogen receptor (ER) are investigated. These compounds should produce a pure antiestrogenic effect without the undesirable partial estrogenic agonist activity associated with some types of antiestrogens1.

 

            Strategically, the aims are to design, synthesise and biologically evaluate a library of structurally related triarylethylene-heterocycle linked compounds containing the modified tamoxifen-type triarylethylene pharmacophore with potential application as selective estrogen receptor modulators (SERMS). These SERMS, or antiestrogens, are designed to occupy the known steroid binding site of the ER together with the adjacent recently reported second ER binding site2. Estrogen receptor antagonists will thus act as carrier prodrugs of cytotoxic drugs.

 

            Computational analyses are routinely performed in order to optimise the molecular design. Sybyl and Macromodel are used to model and dock the novel ER-ligands while an in-house scoring routine provides information on the goodness-of-fit of the ligands. Other methods are also used to optimise the analysis of ligands. These methods are also used to correlate the data from in vitro assays and provide a detailed structure-activity relationship (SAR).

 

            Endoxifen, a tamoxifen metabolite, was chosen as a suitable ligand for the scope of the project. To date, a number of endoxifen analogues have been studied computationally and scored according to their suitability as an ER anchor for the delivery of a conjugated secondary drug. The best analogues will be synthesised and biologically evaluated.

 

 

1 Robertson, J.F.R. (2004) Cancer Treatment Reviews 30: 695-706

2 De Angelis, M., Stossi, F., Carlson, K.A., Katzenellenbogen, B.S., Katzenellenbogen, J.A. (2005) J. Med. Chem. 48: 1132-1144

 

 

 

 

 

This work is supported by IRCSET - the Irish Research Council for Science, Engineering and Technology, funded by the State through the National Development Plan.

 

 

 

 

 

Molecular docking for substrate identification: Lessons learnt from the family of Short-Chain Dehydrogenase/Reductases

 

Angelo Favia1, Janet M. Thornton1 and Irene Nobeli2

 

1. European Bioinformatics Institute – EMBL, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK

2. Randall Division of Cell and Molecular Biophysics, New Hunt’s House, Guy’s Campus, King’s College London, London SE1 1UL, UK

 

      As structural genomics initiatives contribute to an ever-increasing number of protein

structures, we have now access to many proteins for which the three dimensional arrangement

of atoms is known, but the biochemical function is either totally, or partially, unknown. The

functional information that can be derived from the amino acid sequence alone is limited, and

hence structure-based prediction of the function of a protein is currently a hot topic, and one

that is being addressed by many bioinformatics groups across the globe.

Molecular docking, the process of identifying and ranking the binding poses of a ligand to a

protein is a technique that has long been established as a useful tool in drug design and lead

identification. It is generally acknowledged that modern docking programs can help with the

identification of good binders, even though they have had considerably less success in the

prediction of actual binding energies for a variety of protein families. Although widely used

in the search for inhibitors, docking is more recently being investigated as a tool for protein

function identification. More specifically, recent publications have claimed considerable

success in identifying both known and unknown substrates of proteins.(Kalyanaraman et al.

2005; Hermann et al. 2006). In our previous work, we had found it considerably harder to

identify a protein’s substrate when cross-docking a large number of enzymes and their

cognate ligands.(Macchiarulo et al. 2004) Hence, we decided to revisit this problem and

examine the use of docking in identifying the substrates of a single protein family with a

remarkable substrate diversity, the short-chain dehydrogenases/reductases (SDRs).

Here, we examine different protocols for identifying candidate substrates for 27 SDR proteins

of known catalytic function. We present the results of docking a) the cognate substrates and

products of these proteins, b) approximately 900 metabolites from the human metabolome

and c) the whole of the KEGG Ligand database to each of these proteins. More specifically,

we examine the ability of docking to a) reproduce a viable binding mode for the substrate, b)

rank the substrate highly among the dataset of other metabolites, and c) provide us

information about the nature of the substrate, based on the best-scoring metabolites in the

dataset. We compare two different docking methods and two alternative scoring functions for

one of the docking methods, and attempt to rationalise both the successful and failed cases.

Finally, we introduce a new protocol, whereby we dock only a set of representative structures

to each of the proteins, in the hope of reducing the computational cost resulting from having

to dock a very large number of metabolites to each binding site. We compare the results from

this protocol to our original docking experiments and assess the feasibility of using the

structural representatives, as opposed to very large datasets.

 

References:

Hermann JC, Ghanem E, Li Y, Raushel FM, Irwin JJ et al. (2006) Predicting substrates by docking

high-energy intermediates to enzyme structures. J Am Chem Soc 128(49): 15882-15891.

Kalyanaraman C, Bernacki K, Jacobson MP (2005) Virtual screening against highly charged active

sites: identifying substrates of alpha-beta barrel enzymes. Biochemistry 44(6): 2059-2071.

Macchiarulo A, Nobeli I, Thornton JM (2004) Ligand selectivity and competition between enzymes in

silico. Nat Biotechnol 22(8): 1039-1045.

 

 

 

Modelling of Enzyme Regioselectivity in Tryptophan 7-Halogenase

 

Tatyana Karabencheva and Adrian Mulholland

 

Centre for Computational Chemistry, School of Chemistry, University of Bristol

Bristol BS8 1TS, UK

 

Tryptophan 7-halogenase is a new type halogenating enzyme. It catalyzes the reaction of chlorination at 7 position of tryptophan which is a first step of biosynthesis of antibiotic compound pyrrolnitrin. The enzyme exhibits very high regioselectivity and substrate specificity.

We present here our modelling study of two reaction steps of the most probable mechanism: generation of the chlorination agent - hypochlorous acid and the electrophilic aromatic substitution of tryptophan. We have used QM/MM methodology at semiempirical levels for the quantum part and CHARMM22 force field for the rest of the system. The role of the protein environment in stabilizing of important species along both reactions is analyzed.

This work is supported by ORS, University of Bristol and School of Chemistry fellowships.

 

 

Mechanisms of Membrane Enzymes: Insights from QM/MM Modelling

 

Christo Christov and Adrian Mulholland

 

Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, UK

 

 

Monotopic membrane enzymes such as cyclooxygenase and monoamine oxidase are pharmaceutically important class of drug targets. Their biological functions are realized in heterogeneous environment – water and membrane lipids. Therefore understanding of their mechanisms is much complex and requests application of multilevel modelling methods (www.intbiosim.org).

 

Here we present our QM/MM modelling study on the reaction mechanisms of cyclooxygenase 1 (COX-1) and monoamine oxidase B (MAO-B). In the case of COX-1 first reaction step we used UB3LYP/6-31G* for the quantum part and CHARMM22 force field for the rest of the system. MAO-B mechanism was modelled at PM3/CHARMM and B3LYP/6-31+G(d)//PM3-CHARMM levels. Analysis of stabilization of stationary points on the reaction path is done.

 

This work is part of IntBioSim project, supported by BBSRC

 

 

 

Novel Monte Carlo methods for sampling the protein backbone

 

Juan Fernandez Carmona

 

University of Southampton School of Chemistry

Email: j.fernandez-carmona@soton.ac.uk

 

 

Understanding protein 3D structure is one the major challenges in molecular modeling. Activation pathways of proteins may involve major changes in the backbone and often large scale motions for loops.

 

Sampling large scale motion using the Monte Carlo method needs accurate and efficient specific algorithms. The concerted rotation with angle (CRA) appears to be one of the most efficient methods to sample large scale motions.

 

The CRA algorithm has been applied to the lyzozyme protein. In this particular system, large scale motion is observed as the ligand is changed. The ability of this novel sampling algorithm to capture this motion will be described.

 

Bibliography

J. P. Ulmschneider, W. L. Jorgensen, Monte Carlo backbone sampling for polypeptides with variable bond angles and dihedral angles using concerted rotations and a Gaussian bias, J. Chem. Phys., 2003, 118, 4261-4271.

 

L. R. Dodd, T. D. Boone, D. N. Theodorou, A concerted rotation algorithm for atomistic Monte Carlo simulation of metals and glasses, Molecular Physics, 1993, 78, 961-996.