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Workshop location: Fiesta Resort Conference Center
	SUNDAY, May 9th
TIME	EVENT
3:00pm	Hotel Check-In
5:30-7:00pm	Workshop Registration - Galleria Foyer
7:00-8:30pm	Social Reception & Cocktails (Cash Bar)-Encantada Patio

MONDAY, May 10th
	WORKSHOP SESSIONS
TIME	EVENT	TITLE/ABSTRACT
8:00-8:30am	BREAKFAST - Encantada I & II
8:35-8:45am	Welcome Remarks - Mike Thorpe & Banu Ozkan
8:45-9:30am	Ken Dill	Aspects of protein physics that are independent of amino-acid sequence Not all of the physical properties of proteins depend on their amino acid sequences. An increasing number of properties of proteins can be understood simply on the basis of analytical polymer models and simple scaling arguments. For example, the thermal properties of protein stability -- free energies, enthalpies, entropies, and heat capacities of protein folding -- are found to depend mainly on the protein's chain length. Such models can be used to draw inferences about the proteomic stabilities of cells. In addition, aspects of protein crystallization and fibrillization can also be predicted without detailed atomic information or amino acid sequence.
9:35-10:20am	Les Dutton	Catalytic capacity of helical bundles Starting from scratch, alpha-helix bundles comprising initially just E, K and L can be altered in an orderly fashion to assemble in singular form a range of different redox and photoactive cofactor structures. Spectral and redox and acid-base potentials of the cofactors can be modified to extents typical of enzymes. Moreover, with a selected cofactor, the bundles can be persuaded to perform distinct functions analogous to natural enzymes such as oxygen binding as in heme globins, superoxide generation as in neutrophils and quinol-cytochrome c reductase activity as in oxidative energy metabolism. External residues of the bundles prove highly adaptable for assembly on surfaces or incorporation into lipid bilayers while conserving activity. The remarkable adaptability of these synthetic proteins is possible because, unlike their natural counterparts, we can actively manage complexity to maintain simplicity.
10:25-10:40am	Morning Break
10:45-11:30am	Susan Marqusee	Walking the landscape one step at a time
11:35am-12:20pm	Lisa Lapidus	Finding the True Speed Limit of Protein Folding Many studies over the past decade have endeavored to find the “speed-limit” of folding by measuring isolated loops, helices and hairpins and by finding small proteins that fold on the microsecond timescale. While these studies have determined the physical speed limit, just as in rush-hour traffic, the real speed limit may be much lower due to transient intramolecular interactions. The method of Trp-Cys contact quenching has revealed a wide range of intramolecular diffusion coefficients in various sequences and concentrations of denaturant. By coupling this technique to a microfluidic mixer, we have recently measured intramolecular diffusion within the B1 domain of protein L during folding and found it to be 2-3 orders of magnitude slower than in high denaturant. Folding rates can be fit to a Kramers’ model with a denaturant-dependent diffusion coefficient, and under physiological conditions folding appears to be limited by diffusion of unfolded conformations.
12:30-1:50pm	LUNCH - Encantada III
2:00-2:45pm	Phil Williams	Simulation and Experimental Force-Induced Unfolding: A study of von Willebrand Factor Related Disease Through studying the force-dependence of the lifetime of the folded state, kinetic parameters of unfolding rate and information of the energy landscape traversed during the force-induced unfolding can be extracted. To probe further the unfolding process, the effect of single conservative mutations on the kinetics and landscape may be studied, and computational models run in an attempt to follow the experiment at the atomistic level. Such studies have suggested that (a) the force-induced unfolding pathway is often different to the force-free pathway, and (b) the discrepancy in timescale (and hence force) between experiment and simulation significantly complicate any comparison. Here, I will discuss the development of a new paradigm for the simulation of protein unfolding and benchmark its application on the well-studied titin I27 system. I will show how the method can predict the shape of the energy landscape explored during the force experiment by accurately predicting the location of energy minima and maxima, and that the method can predict both experimental forces and the effect of mutation on the unfolding behaviour. I will then discuss the application of the method to the forced-induced unfolding of the A2 domain of the blood clotting protein von Willeband Factor: Force-induced unfolding of the protein, created through hydrodynamic drag on this domain, is known to occur naturally within the circulation. A variety of diseases exist associated with single residue mutations in the protein that lead to altered unfolding propensity giving rise to bleeding/clotting disorders. Simulations of the force-induced unfolding of A2 under physiological forces (25 pN) reveal a strong correlation between the residues which lose contacts on the onset of unfolding and those which are present in disease. The results show how the mechanical strength of a protein under low forces is a global property and affected by changes in the structure and/or dynamics of the molecule a distance from where the force is being applied.
2:50-3:35pm	Adam de Graff	Geometric Pathways in Biomolecules The static structure of biomolecules contains valuable information regarding their flexibility and hence potential for internal motion. Using rigidity theory, we will discuss how a static biomolecular structure and its geometric constraints can be analyzed to reveal rigid and flexible regions. While rigidity analysis indicates the potential for internal motion, a dynamic model is necessary to explore the amplitudes. For this purpose, we will describe a new protein modeling technique developed in the Thorpe group called Geometric Simulation that efficiently explores the available conformational space given a set of constraints. A new webserver will also be introduced that finds stereo-chemically acceptable pathways between two structures. The method can also be applied to cases for which the set of constraints is dynamic. This is particularly important when predicting pathways for classes of proteins that undergo unfolding under an applied load. We will demonstrate how strain analysis and simple bond breaking rules can be used to predict unfolding pathways of proteins from their native structure.
3:40-3:55pm	Afternoon Break
4:00-4:45pm	Chihta Chia
4:50-5:35pm	John Moult	Successes and otherwise in CASP, with implications for protein folding
5:35pm	Poster Session - Encantada I & II
6:00pm	Cocktails (Cash Bar) - Galleria A & B
6:30pm	Dinner (with Cash Bar) - Galleria A & B

TUESDAY, May 11th
	WORKSHOP SESSIONS
TIME	EVENT	TITLE/ABSTRACT
8:00-8:40am	BREAKFAST - Encantada I & II
8:45-9:30am	Rohit Pappu	Predicting the phase behavior of archetypal intrinsically disordered proteins and implications for functional mechanisms Intrinsically disordered proteins (IDPs) adopt heterogeneous ensembles of conformations under physiological conditions. It is important to understand the relationship between amino acid sequence and conformational ensembles of IDPs because this might clarify how disorder is used in physiological function. Studies of archetypal IDPs i.e., sequences with low overall hydrophobicity such as polar tracts and sequences with varying amounts of net charge lead to the proposal of a protein phase diagram that enables the prediction of polymeric attributes for IDP conformational ensembles using easily calculated physico-chemical properties of amino acid sequences. Tools from theory, simulation, and experiment are being combined to yield insights regarding the implications of IDP phase behavior for the development of quantitative measures of protein disorder and for mechanistic models that explain the role of disorder in protein function.
9:35-10:20am	Emanuele Paci	Thermodynamics, kinetics and mechanics of structured and unstructured polypeptides The possibility of monitoring the conformation of single proteins and finely perturb their energy landscape made possible by the development of highly sensitive mechanical probes has opened a new window onto the properties of these complex molecules. I will present some recent experimental results, which confirm theoretical predictions of “anomalous” unfolding kinetics and discuss the danger of excessively simple projections when studying protein free-energy landscapes. I will also present some recent results, which show how a thorough analysis of rapid intrachain kinetics of disordered or marginally structured peptides reveals complex and sequence-specific properties of their free-energy landscapes. Both sets of results have some important consequences on the function and disfunction of proteins in the cell.
10:25-10:40am	Morning Break
10:45-11:30am	Ileana Streinu	How far can you reach? A protein backbone can be modeled mechanically as a robot arm (or chain) with revolute joints. The "Reach problem" asks for a characterization, and an efficient algorithm, for the maximum and minimum distances between the chain's endpoints. This has been a long standing open problem in robotics. Formulated as an optimization of a quadratic function over a set of algebraic constraints, it has been approached, in practice, with classical gradient descent heuristics, with no guarantee of correctness (due to the lack of criteria for distinguishing local from global extrema) and no bounds on the running time. Our recent results completely settle the theoretical characterization of extremal reaches, and offer surprisingly efficient algorithmic solutions in cases of practical importance. This is joint work with Ciprian Borcea.
11:35am-12:20pm	Meera Sitharam	Atlases of molecular packing configuration spaces: description, efficient computation, application in viral assembly modeling
12:30-1:50pm	LUNCH - Encantada III
2:00-2:45pm	Dave Thirumalai	Characterizing Unfolded States of Proteins: Molecular Transfer Model
2:50-3:35pm	Jane Dyson	Functional Marginally-Folded Proteins Examples of functional proteins exist on a continuum from fully folded to fully unfolded. Many interacting protein domains fold completely only in the presence of their binding partners. Complex formation does not always result in an increase in the "foldedness" of a protein, and the range of stabilities that are visited by a given protein chain under various conditions is frequently intimately related to its function. Two examples will be introduced where solution structural and dynamic studies identify molten globule-like states that mediate important functions of proteins.
3:40-3:55pm	Afternoon Break
4:00-4:45pm	Carlos Simmerling	Improving force fields for protein dynamics and folding: Amber ff10SB The quality of a simulation is dependent on the accuracy of the underlying energy function. We recently published a set of updated protein backbone dihedral parameters, ff99SB, that was based on gas-phase QM calculations for peptides. Although it has been very successful, we noted slight disagreement with NMR solution data. We have made minor adjustments to the backbone parameters to improve agreement. More significantly, the side chain dihedral parameters are 15 years old and many have serious errors. We refit these parameters using QM calculations for over 5,000 conformations. The last part of the talk will present an improved GB implicit solvent model that was refit to PB and explicit solvent calculations.
6:00 pm	Cocktails (Cash Bar) - Encantada II & III
6:30 pm	Banquet Dinner (with Cash Bar) - Encantada II & III

WEDNESDAY, May 12th
	WORKSHOP SESSIONS
TIME	EVENT	TITLE/ABSTRACT
8:00-8:40am	BREAKFAST - Encantada I & II
8:45-9:30am	Banu Ozkan	Protein Foldability and Functional Evolution by Conformational Diversity Using our previously developed method of combining the Zipping Assembly Method with a geometric constraint based search algorithm, along with information from modern day analogues, we predict the structure of three ancestral evolutionary diverged proteins. We predict the structure to ~3Å rmsd from the experimentally determined native state of one of the reconstructed ancestral proteins, and ~1Å rmsd for residues in the binding pocket. We then examine how the function of these proteins evolved by examining the conformational pathway between predicted ancestral structures. We also applied our approach to simulate a repertoire of artificial WW domain sequences Our result shows that coupling information obtained from evolutionary data has a remarkable influence on the local contacts of N-terminal ?-turn of WW domains. This turn would not form correctly if lack of such information.
9:35-10:20am	Silvia Cavagnero	Protein Folding Dynamics on and off the Ribosome The pathways of protein folding in vivo are still poorly understood despite the tremendous impact of correct folding for cell function and disease prevention. In the case of small/medium-size proteins, kinetic arguments suggest there is ample time for cotranslational conformational sampling, while nascent chains are still ribosome-bound and before synthesis of the full length protein is complete. Given the complexity of the cellular environment, a combination of tailored biological and spectroscopic tools is likely needed to drive progress in this area. Current efforts from our group will be presented, with emphasis on the dynamics and spatial confinement of nascent chains, the role of the ribosome in modulating nascent protein motions, and the structural rearrangements that take place upon ribosome-release of fully synthesized nascent proteins.
10:25-10:40am	Morning Break
10:45-11:30am	Maria Kurnikova	Hydrophobic effects in membrane protein assembly and function
11:35am-12:20pm	Jayanth R. Banavar	Geometry and Physics of Proteins Globular proteins are a key component of the network of life. We argue that the results accumulated over the years inexorably lead to a unified framework for understanding proteins. The framework predicts the existence of a fixed menu of folds determined by geometry, clarifies the role of the amino acid sequence in selecting the native-state structure from this menu, and explains the propensity for amyloid formation.
12:30-1:50pm	LUNCH - Encantada III
2:00-2:45pm	Vijay Pande	Insights from atomistic simulations of protein folding on the millisecond timescale and beyond Due to new computational methods, including Markov State Models (MSMs), GPU-based Molecular Dynamics, and large scale distributed computing (eg Folding@home), we can now simulate protein folding on the millisecond timescale, in all-atom detail, with sufficient statisitics to yield non-anecdotal results. What emerges from these simulations is a new paradigm for how proteins fold, in which non-native contacts play an important role and dramatically reshape how we think of the unfolded state (under folding conditions). Moreover, these results have lead to a new simple analytic theory which incorporates these new chemical insights and, when combined with the simulations, yields both a means to quantitatively predict properties of folding for specific proteins as well as a theory for how proteins fold.
2:50-3:35pm	M. Scott Shell	Multiscale strategies for modeling proteins and liquid water Multiscale methods-in which simplified models are coupled to detailed atomic ones-are essential to modeling, predicting, and understanding many process in biology that span large ranges of length and time scales. Here, we discuss recent projects in our group that connect reduced-physics descriptions of biomolecular systems with detailed all-atom simulations of accurate physiochemical models. Central to these efforts is a quantity called the relative entropy, which measures the amount of information lost upon coarse-graining a system into a simpler model. Minimization of this quantity provides a common route for developing both coarse-grained simulation models and simple analytical interpretations of detailed calculations.
3:40-4:00pm	Afternoon Break
4:00-6:00pm	Trip to Desert Botanical Garden
	Dinner on your own

THURSDAY, May 13th
TIME	EVENT
7:30-9:00am	BREAKFAST - Milagros Restaurant
	Concluding Remarks