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Abstracts – Section for Biomolecular Sciences - University of Copenhagen

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Abstracts and Papers

Here you can find teacher abstracts and links to papers for the round table paper discussion sessions.

Mikael Akke Birthe B Kragelund Wolfgang Peti
Lise Arleth Kresten Lindorff-Larsen Kasper D Rand
Thomas Hamelryck Frans Mulder Ben Schuler
Jan H Jensen Lene Oddershede Kaare Teilum

Mikael Akke

Biophysical Chemistry, Lund University


Conformational dynamics is intimately connected to molecular recognition involving proteins in two principal ways. Conformational dynamics contributes both to the kinetics and the thermodynamics of ligand binding. First, conformational transitions between different substates can control access to the binding site (kinetics). Second, differences between free and ligand-bound states in their conformational fluctuations contribute to the entropy of ligand binding (thermodynamics).

In regard to binding kinetics, it is of great interest to understand the underlying protein dynamics and its role in setting the time scale for protein–ligand association into the final complex. A minimal framework for investigating ligand binding involves two different pathways: the induced-fit pathway and the conformational-selection (or select-fit) pathway, the relative importance of which has been the subject of recent investigations. I will describe results from NMR relaxation dispersion experiments that serve to map the conformational changes of a protein, as it moves across the energy landscape from the free state to the ligand-bound state.

Conformational entropy has been shown to contribute significantly to binding affinity, selectivity, and allostery. NMR relaxation experiments provide a unique probe of conformational entropy by characterizing fast bond-vector fluctuations at atomic resolution. By monitoring differences between the free and ligand-bound states in their backbone and side-chain order parameters, one can estimate the contributions from conformational entropy to the free energy of binding. This approach can be combined favorably with molecular dynamics simulations to provide increased coverage of the sampled degrees of freedom.


  1. Tzeng & Kalodimos (2012) Protein activity regulation by conformational entropy Nature 488:236-240
  2. Brüschweiler et al. (2009) Direct Observation of the Dynamic Process Underlying Allosteric Signal Transmission J Am Chem Soc 131:3063-3068

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Lise Arleth

Niels Bohr Institute, University of Copenhagen, Denmark


The lecture by Lise Arleth will provide a short overview of the general use of X-rays and neutrons in structural and dynamical investigations of biological molecules and a short overview of the present development within large scale facilities for X-rays and neutrons. A more elaborate overview will then be provided on one of the small-angle scattering (SAS) technique, which is one of the most popular techniques for obtaining structural information about biological molecules in solution. In particular, it will be discussed what can be obtained through, respectively, X-ray and neutron based small-angle scattering (SAXS and SANS).

Core messages of the presentation:

  • X-rays and neutrons in the investigation of structure and dynamics of biological molecules: X-rays and neutrons are very commonly applied to investigate structural properties of biological systems. In particular, synchrotron X-ray based protein crystallography has lead to the vast majority of structural information about proteins down to atomic resolution in the Protein Data Bank. With respect to investigations of structural dynamics, both X-rays and neutrons have very interesting properties that clearly enables structural investigations on a broad range of both time and length scales, but that is very far from being fully exploited or even understood.
  • Large Scale facilities for X-ray and neutron Scattering: The majority of the X-ray based investigations and all the neutron based investigations are performed on international large scale research facilities. Both in Europe and internationally, new and much more powerful large scale facilities for X-ray and neutron scattering are being commissioned in these years. With time, these facilities will allow for bringing specialized techniques and approaches out to a much broader range of users.
  • SAXS and SANS in the investigation of structure and dynamics of biological molecules in solution: The functioning of proteins is generally coupled to structural transitions and structural flexibility of the proteins. These are inherently challenging to study with protein crystallography, but are straight forwardly studied with solution Small-Angle X-ray Scattering (SAXS) and its sister technique, small-angle neutron scattering (SANS). Both techniques resolve the structure of particles in the 10-1000 Ångstrøm range and have very few limitations with respect to sample and buffer conditions. During the last few years, the strength of small-angle scattering has become very clear due to an enormous improvement of both the instrumentation and the data analysis techniques. Examples of the usage of small-angle scattering in the investigation of complex biological structures will be provided, and the path to obtain dynamical information will be discussed.

The discussion in the afternoon workshop will focus on recent work and perspectives for the investigation of the structure and dynamics of membrane proteins in more native environments through the reading of the following three articles:


  1. Andersson et al. (2009) Structural Dynamics of Light-Driven Proton Pumps Structure 17:1265-1275
  2. Kynde et al. (2014) Small-angle scattering gives direct structural information about a membrane protein inside a lipid environment Acta Cryst. D 70:371-383
  3. Feld and Frank (2014) Enabling membrane protein structure 
and dynamics with X-ray free electron lasers Curr Opin Struct Biol 27:69–78

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Thomas Hamelryck

Department of Biology, University of Copenhagen, Denmark


The inference of protein structure from experimental data or from the protein sequence alone or is essentially a problem in probabilistic inference. State-of-the-art Bayesian machine learning methods are increasingly used to address current bottlenecks in protein structure determination and prediction, including the inference of protein ensembles that reflect a protein's dynamical properties. This talk will provide a gentle introduction to Bayesian inference and its emerging role in the inference of protein structure and dynamics.


  1. Olsson et al. (2011) Generative probabilistic models extend the scope of inferential structure determination J Magn Res 213:182-186
  2. Olsson et al. (2014) Probabilistic Determination of Native State Ensembles of Proteins J Chem Theory Comput DOI: 10.1021/ct5001236
  3. Boomsma et al. (2008) A generative, probabilistic model of local protein structure PNAS 105: 8932–8937

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Jan H Jensen

Department of Chemistry, University of Copenhagen, Denmark


In my talk I'll introduce the program Propka ( which can predict the pKa values of ionizable groups in proteins and protein-ligand complexes from the protein structure.  I'll also talk about how these pKa values can be used to predict pH dependent properties of proteins, such as the charge of an amino acid, isoelectric point, enzymatic activity, stability, and protein-ligand and protein-protein binding free energies


  1. Søndergaard et al. (2011) Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of pKa Values J Chem Theory Comput 7:2284-2295
  2. Olsson et al. (2011) PROPKA3: Consistent Treatment of Internal and Surface Empirical pKa Predictions J Chem Theory Comput 7:525-537 
  3. Kongsted et al. (2007) Prediction and Rationalization of the pH Dependence of the Activity and Stability of Family 11 Xylanases Biochemistry 46:13581-13592

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Birthe B Kragelund

Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Denmark


Membrane proteins play central roles in cellular signalling processes The intracellular domains contain large intrinsically disordered regions of importance for function with numerous predicted as well as confirmed phosphorylation sites. Due to their lack of globular structure insight into their structure-function relations have been crucially lacking. Using NMR spectroscopy, biophysics and cell-biology regulatory roles of intrinsic disorder in cytokine receptors and in ion transporters with direct links to phosphorylations will be addressed. The interplay of intrinsic disorder and phosphorylation in these proteins highlights specific space and temporal effects in scaffolding including interplay with some of the major signaling pathways such as JAK2/STAT and MAPK-signaling. 


No paper discussion session...

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Kresten Lindorff-Larsen

Department of Biology, University of Copenhagen, Denmark


All-atom molecular dynamics simulations provide a vehicle for capturing the structures, motions, and interactions of biological macromolecules in full atomic detail. Such simulations have, however, been limited both in the timescales they could access and in the accuracy of computational models used in the simulations. I will begin by presenting briefly how progress has been made in both of these areas so that it is now possible to access the millisecond timescale, and how we have been able to parameterize relatively accurate energy functions.

I will then present recent results that highlight how such long-timescale simulations have been used to provide insight in to the structural and folding dynamics of proteins. In the area of protein folding, such simulations have for example helped to suggest common principles that underlie the folding process of fast-folding proteins. I will also describe how molecular dynamics simulations, when integrated with NMR experiments, can help provide insight into the structural dynamics of proteins.


  1. Lindorff-Larsen et al. (2011) How Fast-Folding Proteins Fold Science 334: 517-520
  2. Best (2012) Atomistic molecular simulations of protein folding Curr Opin Struct Biol 22:52-61
  3. Lindorff-Larsen et al. (2012) Systematic Validation of Protein Force Fields against Experimental Data PLoS One 7:e32131

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Frans Mulder

University of Aarhus, Denmark


All proteins studied to date show a rapid onset in their dynamics around 220 K, when sufficiently hydrated. A large change in heat capacity is associated with this transition, as in the case of semi-crystalline solids, which undergo a transition from hard and relatively brittle state into a molten or rubber-like state. The term ‘glass transition’ has therefore also been applied to protein powders, but it is likely more correct to just refer to it as a ‘dynamical transition’. Since this dynamical transition has been correlated with the onset of function in enzymes there is a lot of interest in understanding the origin of the transition.

Various spectroscopic studies have increased our understanding of the phenomenon over the past decades. Here we will discuss NMR spectroscopic and neutron scattering data applied to proteins, which have shed new light on the process. I will present temperature-dependent protein dynamics studies, where NMR data are integrated with neutron scattering to investigate the protein glass transition. I will also touch upon the usage of molecular biology tools for specific isotope labeling, which can be applied to both fields.


  1. Lee and Wand (2001) Microscopic origins of entropy, heat capacity and the glass transition in proteins Nature 411:501-504
  2. Wood et al. (2013) Protein surface and core dynamics show concerted hydration-dependent activation Angew Chem Int Ed Engl 52:665-668;jsessionid=32427014D4559C9186635BF028B5321A.f04t01

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Lene Oddershede

Niels Bohr Institute, University of Copenhagen, Denmark


Novel force-scope techniques allow for precise measurements of the strength, structure and dynamics of individual molecules, even within living cells. Observation of a single molecule can reveal information on spatial and temporal inhomogeneities that are hidden in ensemble measurements and are particular useful for uncovering protein dynamics. During the last 10-20 years that has been a major leap in the development of single molecule force spectroscopy techniques, the three most widespread techniques being optical tweezers, magnetic tweezers, and atomic force spectroscopy. These techniques have proven extremely successful in uncovering the function and dynamics of individual proteins, for instance the action of regulatory proteins or molecular motors. Also, force spectroscopy is being used to uncover the structural properties and folding dynamics of proteins, thus revealing, e.g., the existence of temporary intermediate states with important biological functions. During the discussion session all participants will, through an applet, get hands-on experience with optical tweezers and for each of the single molecule techniques, its capabilities, typical measurements, potential and limitations will be discussed. Also, we will discuss optimal routes for experiments focused on unravelling the dynamics of functional proteins.


  1. Oddershede (2012) Force probing of individual molecules inside the living cell is now a reality Nat Chem Biol 8:879-886.
  2. Yua et al. (2012) Direct observation of multiple misfolding pathways in a single prion protein molecule PNAS 109:5283-5288.
  3. Woodside and Block (2014) Reconstructing folding energy landscapes by single-molecule force spectroscopy Ann Rev Biophys 43:19-39

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Wolfgang Peti

Brown University, USA


It has become clear that dynamics of proteins that occur on a large variety of timescales are critical for their function and thus control the underlying biological processes they regulate. Well-folded proteins that possess stable 3D structures have significantly different functional profiles than highly dynamic IDP-type proteins. Interestingly, it has become evident that IDP-like domains, e.g. flexible C-terminal domains, can profoundly influence protein dynamics on structured domains and also play a critical role in protein:protein recognition events. We will discuss these effects by analyzing the importance of protein dynamics of phosphorylation enzymes and their regulation. 


  1. Krishnan et al. (2014) Targeting the disordered C terminus of PTP 1B with an allosteric inhibitor Nat Chem Biol 10:558-566
  2. Francis et al. (2011) Structural basis of p38a regulation by hematopoietic tyrosine phosphatase Nat Chem Biol 7:916-924
  3. Koveal et al. (2013) Ligand Binding Reduces Conformational Flexibility in the Active Site of Tyrosine Phosphatase Related to Biofilm Formation A (TpbA) from Pseudomonas aeruginosa J Mol Biol 425: 2219-2231
  4. Kornev et al. (2006) Surface comparison of active and inactive protein

    kinases identifies a conserved activation mechanism PNAS 103:17783–17788

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Kasper D Rand

Department of Pharmacy, University of Copenhagen, Denmark


The role of subtle changes in protein mobility and structural flexibility in the regulation of protein function is becoming increasingly evident. Sensitive, high-resolution techniques are needed to detect the elusive dynamic interplay of distant sites critical for protein function. The hydrogen/deuterium exchange (HDX) of main-chain amides is highly sensitive to dynamic changes in conformation between protein states, and report on the overall flexibility of the protein backbone and local hydrogen bonding (i.e. conformational dynamics). Mass spectrometry (MS) has evolved to be a powerful technique to measure protein HDX and thus monitor protein dynamics in solution, due to tolerance to complex protein systems, buffer composition and low sample concentration. More recently, the integration of electron transfer dissociation (ETD) into the HDX-MS workflow has enabled the mapping of conformational changes in proteins at a spatial resolution down to individual residues.

This lecture will give an overview of how to measure the hydrogen/deuterium exchange of proteins by mass spectrometry and how this information can be used to detect and map conformational differences between functional protein states or protein-ligand complexes.


  1. Underbakke et al. (2014) Nitric Oxide-Induced Conformational Changes in Soluble Guanylate Cyclase Structure 22:602-611
    ommentary: Tracking Allosteric Propagation with HX-MS
  2. Rand et al. (2006) Allosteric Activation of Coagulation Factor VIIa Visualizedby Hydrogen Exchange J Biol Chem 281:23018-23024
  3. Rand (2013) Pinpointing changes in higher-order protein structure by hydrogen/deuterium exchange coupled to electron transfer dissociation mass spectrometry Int J Mass Spec 338:2-10

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Benjamin Schuler

University of Zurich, Switzerland


Single-molecule spectroscopy provides new opportunities for investigating the structure and dynamics of unfolded and intrinsically disordered proteins (IDPs). The combination of single-molecule Förster resonance energy transfer (FRET) with nanosecond correlation spectroscopy, microfluidic mixing, and related methods can be used to probe intramolecular distance distributions and reconfiguration dynamics on a wide range of time scales, and even in heterogeneous environments. In view of the large structural heterogeneity of these systems, a description in terms of polymer physical principles is often a useful way of conceptualizing their behavior. I will provide a methodological introduction illustrated with examples ranging from the influence of amino acid composition, charge interactions, temperature, and macromolecular crowding on the structure and dynamics of unfolded proteins and IDPs.


  1. Schuler (2012) Single-molecule FRET of protein structure and dynamics - a primer J Nanobiotech 11:S2
  2. Müller-Späth et al. (2010) Charge interactions can dominate the dimensions of intrinsically disordered proteins PNAS 107:4609–14614
  3. Soranno et al. (2012) Quantifying internal friction in unfolded and intrinsically disordered proteins with single-molecule spectroscopy PNAS 109:17800–17806 

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Kaare Teilum

Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen


Several intrinsically disordered proteins (IPDs) form ordered structures when they bind to other proteins (folding upon binding). Regions of IDPs that in the unbound state form transient secondary structure often coincide with regions that form well-ordered secondary structure in the bound state. How such transient structures modulate the binding is not clear. This is exemplified by two extreme models that suggest opposite effects of transient structure. The conformational selection model for ligand binding predicts that increasing native secondary structure in the ligand-free state increases the association rate, whereas the ‘fly-catching’ model predicts that increasing disorder will increase the association rate by the larger efficient interaction radius of a disordered protein. We will discuss how NMR spectroscopy can be used to characterize transient structures in IPDs, and how this combined with systematic mutational strategies and stopped-flow kinetic measurements can provide insight into the mechanism of folding upon binding. The inherent difficulty to conclusively prove a multi-step mechanism from kinetic data will also be discussed.


  1. Rogers et al. (2014). Coupled folding and binding of the disordered protein PUMA does not require particular residual structure. J Am Chem Soc 136:5197–5200.
  2. Iesmantavicius et al. (2014) Helical propensity in an intrinsically disordered protein accelerates ligand binding Angew Chem Int Ed 53:1548–1551.
  3. Kiefhaber et al. (2012). Dynamics and mechanisms of coupled protein folding and binding reactions. Curr Opin Struct Biol 22:21–29.

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