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Seminars (SMC)

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Event When Speaker Title Presentation Material
SMCW01 20th January 2004
15:30 to 16:30
ME Fisher Theory for molecular motors: may be predictive?
SMC 20th January 2004
17:15 to 18:00
Towards a predictive biology
SMCW01 21st January 2004
09:00 to 10:00
Cellular modelling of cancer - do we have the tools?
SMCW01 21st January 2004
10:00 to 11:00
Intracellular signalling in a molecular jungle: insights from bacterial chemotaxis

The set of biochemical reactions by which an E. coli bacterium detects and responds to distant sources of attractant or repellent molecules is probably the simplest and best understood example of a cell signalling pathway. The pathway has been saturated genetically and all of its protein components have been isolated, measured biochemically, and their atomic structures determined. We are using detailed computer simulations, tied to experimental data, to ask how the pathway works as an integrated unit. Increasingly we find that the physical location of molecular components within the molecular jungle of the cell interior is crucial for an understanding of their function.

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SMCW01 21st January 2004
11:30 to 12:30
S Leibler Genetic and biochemical networks: a physicist's perspective
SMCW01 21st January 2004
14:00 to 15:00
Integrating biological physics into the undergraduate curriculum: the US National Academy report and beyond
SMCW01 21st January 2004
15:30 to 16:30
J-P Hansen Simple models for ion channels: selectivity, intermittency and ion transport
SMCW01 22nd January 2004
09:00 to 10:00
Protein folding kinetics: some new twists on the transition state idea

Some proteins fold very rapidly and with single-exponential kinetics. Despite this simplicity, the underlying microscopic processes are heterogeneous. Different molecules fold along different micro-routes. The energy landscapes are funnel-shaped. What are the routes and the rate-limiting steps? We explore the folding process with master equations. We find that the bottlenecks are sometimes heterogeneous. The reason for the folding speed is that proteins can fold via "zipping": multiple small localized optimization steps, rather than a single global optimization.

SMCW01 22nd January 2004
10:00 to 11:00
Random design: a litany of ignorance
SMCW01 22nd January 2004
11:30 to 12:30
Genomic data and prediction: the value of comprehensive information
SMCW01 23rd January 2004
09:00 to 10:00
The roles of the chemical sciences in predictive biology
SMCW01 23rd January 2004
10:00 to 11:00
R Templer Who cares about lipids anyway?

Open any Cell Biology textbook and you will see that the lipid component of the membrane is essentially boring. As far as the Singer and Nicholson model is concerned the lipid bilayer is simply an impermeable, two-dimensional, liquid partitioner of the cellular compartments. The great majority of Cell Biologists therefore believe that lipids play no further role in the inner functioning of the cell, rather that they passively follow the behaviour of the cell’s only truly active components - the proteins, the DNA and its associated machinery. I will present evidence that strongly suggests that this picture is simplistic, and that proteins and lipids interact in a complex way, regulating each others behaviour.

SMCW01 23rd January 2004
11:30 to 12:30
Rotary motors
SMC 27th January 2004
09:30 to 10:30
The worm turns: the Helix-Coil wormlike chain
SMC 29th January 2004
09:30 to 10:30
DTF Dryden Type I DNA restriction enzymes: smart molecular machines
SMC 3rd February 2004
11:30 to 12:30
How the ear listens: spontaneous mechanical oscillations by mechanosensory hair cells
SMC 5th February 2004
11:30 to 12:30
Elastic theory of a single DNA molecule
SMC 9th February 2004
11:30 to 13:00
Phase separation in biomembranes
SMC 11th February 2004
11:30 to 13:00
Active gels and cytoskeletal dynamics
SMC 17th February 2004
11:30 to 12:30
In silico studies of cell motility
SMC 18th February 2004
11:30 to 12:30
E Carlon Melting of double-stranded DNA-theory and experiments
SMC 19th February 2004
11:30 to 12:30
Probing chromatin dynamics with synthetic DNA ligands
SMC 24th February 2004
11:30 to 12:30
D Andelman The onset of complexation of polymers and DNA with amphiphiles
SMC 25th February 2004
11:30 to 12:30
Crystallization and diffusion of globular proteins in lipid cubic phases
SMC 26th February 2004
11:30 to 12:30
Elastic lever-arm model for myosin V
SMC 2nd March 2004
11:30 to 12:30
Dynamics of active filament solutions
SMC 2nd March 2004
14:00 to 15:00
Membrane fusion
SMC 4th March 2004
11:30 to 12:30
The deformations and Green's response of cross-linked biopolymer networks
SMC 9th March 2004
11:00 to 12:00
Workshop on histone complexation in chromatin
SMC 10th March 2004
11:30 to 12:30
Structural studies of the giant protein titin
SMC 10th March 2004
14:00 to 15:00
R Hawkins Entropic allostery in proteins
SMC 11th March 2004
11:30 to 12:30
Orientational ordering of rod-like polyelectrolytes
SMCW07 15th March 2004
14:15 to 15:00
A Fersht Realistic & predictive simulation?
SMCW07 16th March 2004
09:00 to 10:00
T McLeish & D Wales Features of high dimensional searches
SMCW07 16th March 2004
14:00 to 15:00
E Shakhnovich & D Thirumalai Course-grained view of transition state ensembles
SMCW07 17th March 2004
09:00 to 10:00
Fine-grained simulation of transition state ensembles
SMCW07 17th March 2004
14:00 to 15:00
J Fernandez & P Williams Mechanical folding & unfolding
SMCW07 18th March 2004
09:00 to 10:00
Dynamics of energy landscapes
SMCW07 18th March 2004
14:00 to 15:00
Early events in protein folding
SMC 14th April 2004
11:30 to 12:30
L Mahadevan Statics and dynamics of actin assemblies
SMC 15th April 2004
11:30 to 12:30
Protein dynamics and function
SMC 20th April 2004
11:30 to 12:30
Why bacteria go complex: higher flexibility for better adaptability
SMC 21st April 2004
11:00 to 12:00
V Srivastava The statistical mechanics of brain storage
SMC 22nd April 2004
11:30 to 12:30
T Maggs Simulating the Ether: local algoritms for long-ranged forces
SMC 22nd April 2004
15:00 to 16:00
Functional holography of correlations matrices for biological networks
SMCW05 26th April 2004
12:15 to 13:00
Structural constraints on protein mutations
SMCW05 26th April 2004
13:45 to 14:30
Protein-protein docking by global energy optimisation
SMCW05 26th April 2004
14:30 to 15:30
S Abeln Fold usage on genomes \& protein structure evolution
SMCW05 27th April 2004
10:15 to 11:00
Sequence-structure homology recognition
SMCW05 27th April 2004
11:30 to 12:30
Modelling solvent forces
SMCW05 27th April 2004
13:30 to 14:30
Determination of partially folded states of proteins at atomic resolution
SMCW05 27th April 2004
14:30 to 15:30
Modelling and drug design
SMCW05 27th April 2004
16:00 to 17:00
Case studies in assigning function from structure in structural genomics
SMCW05 28th April 2004
10:15 to 11:00
Ab initio modelling
SMCW05 28th April 2004
11:30 to 12:30
WR Taylor Folds, knots and tangles
SMCW05 28th April 2004
13:30 to 14:30
Identification of interacting sites in protein families
SMCW05 28th April 2004
14:30 to 15:30
Rapper
SMCW05 28th April 2004
16:00 to 17:00
M Madera Comparisons of sequence profiles
SMCW05 28th April 2004
17:00 to 18:00
D Jones Prediction of native disorder in proteins
SMCW05 29th April 2004
10:15 to 11:00
Minimalist protein models and evolution
SMCW05 29th April 2004
11:30 to 12:30
Modelling molecular evolution: Gprotein Coupled Receptors
SMCW05 29th April 2004
13:30 to 14:30
DNA binding sites
SMCW05 29th April 2004
14:30 to 15:30
Mechanics of interfaces in alpha-helical super-coils
SMC 4th May 2004
14:30 to 15:30
Kinetics of self-assembling microtubules: an ``inverse problem" in biochemistry
SMC 5th May 2004
11:30 to 12:30
Cell motility as persistent random motion-``revisited"
SMC 6th May 2004
11:00 to 13:00
Dynamics of intracellular membrane traffic: interacting active networks
SMC 11th May 2004
11:30 to 12:30
RH Colby Reversible aggregation of albumin
SMC 12th May 2004
11:30 to 12:30
A simulation of membrane proteins
SMC 13th May 2004
11:30 to 12:30
Molecular theory of lipid bilayers
SMC 17th May 2004
16:00 to 17:00
Micelle-vesicle transitions in lecithin-bile salt mixtures
SMC 18th May 2004
11:30 to 12:30
A Mogilner Self-organisation of microtubule asters
SMC 19th May 2004
09:30 to 11:00
T Harder From nano-scale cluster to functional platform: lipid raft domains in cell membranes
SMC 19th May 2004
11:30 to 13:00
Immiscible liquid phases in lipid membranes containing cholesterol
SMC 19th May 2004
14:00 to 15:30
Phase separation in binary lipid vesicles
SMC 19th May 2004
16:00 to 17:30
Domains in membranes and vesicles
SMC 20th May 2004
09:30 to 11:00
P Olmsted Shape transformations in phase separated membranes
SMC 20th May 2004
11:30 to 13:00
Active lipid-based organisation on living cell surfaces
SMC 21st May 2004
11:30 to 12:30
Cooperativity principles in protein folding: experimental criteria and interacition nonadditivity
SMC 21st May 2004
14:00 to 15:30
Modelling lipid rafts: size, shape, and possible involvement in membrane mechano-sensitivity
SMC 25th May 2004
11:30 to 12:30
Adsorbed comb-like copolymers as a tool for molecular walkers
SMC 27th May 2004
11:30 to 12:30
D Odde Modeling microtubule self-assembly dynamics during mitosis
SMC 2nd June 2004
09:30 to 16:00
Thinking about evolution in physics and biology
SMC 3rd June 2004
11:30 to 12:30
Highly specific protein-protein interactions, evolution and negative design
SMC 8th June 2004
11:30 to 12:30
M Howard Models for precise protein localisation in bacteria
SMCW03 21st June 2004
13:30 to 14:30
Protein interactions in the context of folding, misfolding \& aggregation

Protein folding is perhaps the most fundamental process associated with the generation of functional structures in biology. There has been considerable progress in the last few years in understanding the underlying principles and dominant interactions that govern this highly complex process. Recently, much research has also focused on the realisation that proteins can misfold in vivo and that this phenomenon is linked with a wide range of highly debilitating diseases that are becoming increasingly prevalent in the modern world. We have been investigating in particular the nature of the amyloidogenic conditions, that include Alzheimer's disease, type 2 diabetes and the spongiform encephalopathies, e.g. BSE and CJD, in which protein misfolding leads to the aggregation of proteins, often into thread-like amyloid structures. Our studies have led us to put forward new ideas concerning the fundamental origins of the various diseases associated with their formation and the various strategies that can be used for their prevention and treatment. We have also speculated more generally that the need to avoid aggregation could be a significant driving force in the evolution of protein sequences and structures.

References:

M. Vendruscolo, J. Zurdo, C.E. MacPhee and C.M. Dobson, “Protein Folding and Misfolding: A Paradigm of Self-Assembly and Regulation in Complex Biological Systems”, Phil. Trans. R. Soc. Lond. A 361, 1205-1222 (2003).

M. Dumoulin, A.M. Last, A. Desmyter, K. Decanniere, D. Canet, G. Larsson, A. Spencer, D.B. Archer, J. Sasse, S. Muyldermans, L. Wyns, C. Redfield, A. Matagne, C.V. Robinson and C.M. Dobson, “A Camelid Antibody Fragment Inhibits the Formation of Amyloid Fibrils by Human Lysozyme”, Nature 424, 783-788 (2003).

F. Chiti, M. Stefani, N. Taddei, G. Ramponi and C.M. Dobson, “Rationalisation of Mutational Effects on Protein Aggregation Rates Using Simple Physical Principles”, Nature 424, 805-808 (2003).

C.M. Dobson, “Protein Folding and Misfolding”, Nature 426, 884-890 (2003).

C.M. Dobson, “In the Footsteps of Alchemists”, Science 304, 1259-1262 (2004).

SMCW03 21st June 2004
14:30 to 15:30
Factors affecting the aggregation of the natively unfolded protein alpha-synuclein

The etiology of Parkinson’s disease is unknown; however, substantial evidence implicates the aggregation of alpha-synuclein as playing a critical role in the disease. We have found that a variety of endogenous and exogenous factors induce a conformational change in alpha-synuclein and directly accelerate the rate of formation of alpha-synuclein fibrils in vitro; other factors inhibit the fibrillation. The mechanism of alpha-synuclein aggregation involves at last three competing kinetic pathways, leading to fibrils, amorphous aggregates, and soluble oligomers. Thus, many factors may cause acceleration of alpha-synuclein fibrillation, and some of these factors are likely to be important in the pathophysiology of alpha-synuclein and Parkinson’s disease. Various aspects of how the self-assembly of alpha-synuclein occurs will be discussed.

Related Links

SMCW03 21st June 2004
16:00 to 17:00
Mesoscopic models for the effect of macromolecular crowding, macromolecular confinement \& surface adsorption upon protein assoc.

A large fraction of the total volume of all biological fluid media is either occupied by soluble macromolecules, or lies within a distance of macromolecular dimension from the surface of an extended structural element such as a cytoskeletal fiber or a membrane. I will describe mesoscopic statistical-thermodynamic models for the excluded volume interaction of a globular protein with inert "background" macromolecules and model boundaries, and for nonspecific weakly attractive interaction between a globular protein and a planar surface. The results of calculations based upon these models will be presented, describing how nonspecific interactions of soluble proteins with features of the local environment are likely to affect specific associations between the soluble proteins. Model predictions will be compared with the result of experiment where relevant data are available.

SMCW03 22nd June 2004
09:00 to 10:00
JM Thornton Protein-protein interactions from a structural perspective

An update of the structural features of multimeric proteins will be presented. We have compiled low redundancy sets of homomeric proteins with different symmetry and subunit composition as well as sets of heteromeric proteins for comparison. We find significant variations between monomers and multimers and with the additional data we compare dimers, trimers, tetramers and hexamers. The variations we observe can all be seen as consequences of the hydrophobic effect, which has long been noted as a major driving force in protein folding and association. A comparison with transient complexes will also be presented.

Ponstingl, H., Kabir, T. & Thornton, J.M. (2003) Automatic Inference of Protein Quaternary Structure from Crystals. J. Appl. Cryst. 36, 1116-1122.

Nooren, I.M.A. & Thornton, J.M. (2003a) Structural characterisation and functional significance of transient protein-protein interactions J. Mol. Biol. 325, 991-1018. PMID: 12527304

Nooren, I. & Thornton, J.M. (2003b) Diversity of protein-protein interactions. EMBO Journal. 22, 3486-3492. PMID: 12853464

SMCW03 22nd June 2004
10:00 to 11:00
Random energy models for interactions and dynamics in the immune response to viruses, vaccines, and cancer

The adaptive vertebrate immune system is a wonder of modern evolution. Under most circumstances, the dynamics of the immune system is well-matched to the dynamics of pathogen growth during a typical infection. Some pathogens, however, have evolved escape mechanisms that interact in subtle ways with the immune system dynamics. In addition, negative interactions the immune system, which has evolved over 400 000 000 years, and vaccination, which has been practiced for only 200 years, are possible. For example, vaccination against the flu can actually increase susceptibility to the flu in the next year. As another example, vaccination against one of the four strains of dengue fever typically increases susceptibility against the other three strains. Immunodominance also arises in the immune system control of nascent tumors--the immune system recognizes only a small subset of the tumor specific antigens, and the rest are free to grow and cause tumor growth.

In this talk, I present a physical theory of original antigenic sin and immunodominance. How localization in the immune system leads to the observed phenomena is discussed.

1) M. W. Deem and H. Y. Lee, ``Sequence Space Localization in the Immune System Response to Vaccination and Disease,'' Phys. Rev. Lett. 91 (2003) 068101.

2) J.-M. Park and M. W. Deem, ``Correlations in the T Cell Response to Altered Peptide Ligands,'' Physica A, to appear.

SMCW03 22nd June 2004
11:30 to 12:30
Domain interactions in multi-domain proteins

Two thirds of all prokaryote proteins, and eighty percent of eukaryote proteins are multi-domain proteins. The composition and interaction of the domains within a multi- domain protein determine its function. Using structural assignments to the proteins in completely sequenced genomes, we have insight into the domain architectures of a large fraction of all multi-domain proteins. Thus we can investigate the patterns of pairwise domain combinations, as well as the existence of evolutionary units larger than individual protein domains. Structural assignments provide us with the sequential arrangement of domains along a polypeptide chain. In order to fully understand the structure and function of a multi-domain protein, we also need to know the geometry of the domains relative to each other in three dimensions. By studying multi-domain proteins of known three- dimensional structure, we can gain insight into the conservation of domain geometry, and the prediction of the structures of domain assemblies.

SMCW03 22nd June 2004
14:00 to 15:00
J Janin A structural basis for the specificity of protein-protein recognition

We compare the geometric and physical chemical properties of interfaces involved in specific and non-specific protein-protein interactions in crystal structures reported in the Protein Data Bank. Specific interactions are illustrated by 70 protein-protein complexes and by subunit contacts in 122 homodimeric proteins; non-specific interactions, by 188 pairs of monomeric proteins making crystal packing contacts selected to bury more than 800 Å2 of protein surface. A majority of these pairs have two-fold symmetry and form ‘crystal dimers’ that cannot be distinguished from real dimers on the basis of the interface size or symmetry. Their chemical and amino acid compositions resemble the protein solvent accessible surface, they are less hydrophobic than in homodimers and contain much fewer fully buried atoms. We develop a residue propensity score to assess preferences for the different types of interfaces, and we derive indexes to evaluate the atomic packing, which is less compact at non-specific than at specific interfaces.

These differences can be interpreted in terms of geometric and chemical complementarity in cases where conformation changes are small and recognition takes place between preformed surfaces. In contrast, large changes at an interface imply that recognition first occurs between surfaces that are not complementary. A basic question in molecular assembly is how this process takes place, and whether we can reproduce it. Molecular docking algorithms that generate protein-protein complexes based on the component structures have been tested in a blind prediction experiment called CAPRI (Critical Assessment of PRedicted Interactions). Results obtained on 13 target complexes indicate that prediction procedures often succeed when the conformation changes are small, although they fail to reproduce large changes.

References:

The structural basis of macromolecular recognition. S.W. Wodak & J. Janin (2002) Adv. Prot. Chem. 61 9-68. Dissecting protein-protein recognition sites. P. Chakrabarti & J. Janin (2002) Proteins 47, 334-343 Dissecting protein-protein interfaces in homodimeric proteins. R.P. Bahadur, P. Chakrabarti, F. Rodier & J. Janin (2003) Proteins 53, 708-719 A dissection of specific and non-specific protein-protein interfaces. R P Bahadur, P Chakrabarti, F Rodier & J Janin (2004) J. Mol. Biol. 336, 943-955

SMCW03 22nd June 2004
16:00 to 17:00
TM Truskett Towards a simple coarse-grained strategy for modelling unfolding, phase separation, and aggregation in protein solutions

Protein stability, aggregation, and crystallization are of fundamental scientific and technological importance. However, molecularly-detailed models that can account for both the proteins and the solvent are computationally prohibitive to study under relevant solution conditions. As a result, the relations between misfolding/aggregation events in solution and protein sequence (mutations), solvent conditions, solution composition, and the presence of interfaces are still poorly understood. Here, we introduce a strategy for investigating these phenomena through use of a new coarse-grained model that combines an analytical theory for heteropolymer collapse with a recently introduced model for solvation in aqeuous solution. This approach can qualitatively reproduce the basic effects of temperature, pressure, and sequence on protein stability. We have used the model to derive effective center-to-center interactions for native and denatured proteins. We are currently using these effective interactions as inputs to liquid-state theory and simulation to gain new insights into the global experimental behavior of protein solutions.

SMCW03 23rd June 2004
09:00 to 10:00
JL Harden Sequence patterning in simple de novo proteins with tailored association behavior

Patterning of charged or hydrophobic residues in repetitive amino acid sequences is often associated with the formation of well-defined assemblies such as helix bundles and beta sheets. In recent years, de novo protein designs have extensively utilized such patterned motifs to construct minimalist sequences that fold or aggregate in a predetermined manner via the specific association of secondary structures. This talk will discuss examples of de novo designs based on associating amphiphilic secondary structures. In particular, we will focus on a series of modular de novo proteins that preferentially form homo- and hetero-trimeric assemblies. The stability of these assemblies and the secondary structure of the associating elements in various solution conditions will be presented and discussed in the context of opportunities for theoretical models of these simple systems

SMCW03 23rd June 2004
10:00 to 11:00
Phase transitions in protein solutions

Dense liquid, gel-like and solid, ordered in three, two, or one dimension, or completely disordered phases form in protein solutions and underlie physiological and patho-physiological, laboratory, and technological processes. The loss of phase stability of the protein solution represents the ultimate form of intermolecular interactions at high solution concentrations. The loss of phase stability can be accompanied by loss of conformational stability, as in the formation of the amyloid fibrils, or occur with preservation of the protein conformation.

Two aspects of the phase transitions will be discussed.

The first one is the role of water, structured at the hydrophobic and hydrophilic patches on the surface of the protein molecules. Examples will be provided illustrating that this structuring often determines the entropy and enthalpy balance of the phase transition, leads to unusual intermolecular interaction potentials with one or more outlying maxima, which severely affect the phase diagrams, and that the dynamics of destruction of the water shell is the major determinant of the kinetics of association of molecules into solid phases. Because of the water structuring, the fastest pathway of nucleation of ordered solid phases is not the one with the lowest free-energy barriers.

The second aspect is the interaction between the phases. Examples from the nucleation of two types of ordered solid phases: three-dimensional crystals and the polymers of sickle cell hemoglobin, which have one-dimensional translational symmetry, show that nucleation proceeds via a disordered liquid-like intermediate. In crystal nucleation, the structuring of the intermediate is the rate determining step in the nucleation process, while in the nucleation of the HbS polymers, the formation of the intermediate determines the overall nucleation rate.

Phys. Rev. Lett. 84, 1339 (2000); Nature 406, 494 (2000); Proc. Natl. Acad. Sci. USA 97, 6277 (2000); Solid State Physics 57, 1 (2002); Proc. Natl. Acad. Sci. USA 100, 792 (2003); Methods in Enzymology 368, 84 (2003); Biophys. J. 85, 3935 (2003); J. Am. Chem. Soc. 125, 11684 (2003); J. Mol. Biol. 336, 43–59 (2004); Crystal Growth and Design 5, in print (2004).

SMCW03 23rd June 2004
11:15 to 12:15
Achieving specificity in regulated protein-protein interactions

The crowded environment of a cell presents an individual protein with a considerable evolutionary challenge if it is to achieve specific 'signal' interactions with authentic macromolecular partners and minimise non-specific 'noise'. Simply maximising the interaction energy of the specific complexes improves the signal-to-noise ratio, but at the price of reversibility. Proteins involved in regulated rather than constitutive complexes, must achieve specificity by more subtle mechanisms, which will be illustrated by examples of macromolecular complexes determined in our laboratory.

Related Links

SMC 23rd June 2004
14:00 to 15:00
Intrinsic disorder and protein function
SMC 24th June 2004
09:30 to 10:30
Thinking about gene regulatory networks
SMC 29th June 2004
09:30 to 10:30
Maintenance and propagation of the blueprint for life Cancer and why DNA matters
SMC 29th June 2004
10:30 to 11:30
S Bell Maintenance and propagation of the blueprint for life The nuts and bolts of DNA replication
SMC 29th June 2004
11:45 to 12:45
A Venkitaraman Maintenance and propagation of the blueprint for life TBA
SMC 29th June 2004
13:45 to 14:45
Maintenance and propagation of the blueprint for life Packaging of DNA and the problems it presents
SMC 7th July 2004
09:30 to 10:30
Baculovirus polyhedrin protein crystallisation in vivo: armour plating for viruses
SMC 7th July 2004
10:30 to 11:30
R Casey Protein crystallization in vivo: Seed proteins
SMC 7th July 2004
12:00 to 12:30
Protein crystallization in vivo: The Why and Why not
University of Cambridge Research Councils UK
    Clay Mathematics Institute London Mathematical Society NM Rothschild and Sons