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1.  Molecular dynamics simulations of transitions for ECD epidermal growth factor receptors show key differences between human and drosophila forms of the receptors 
Proteins  2013;81(7):1113-1126.
Recent X-ray structural work on the Drosophila epidermal growth factor receptor (EFGR) has suggested an asymmetric dimer that rationalizes binding affinity measurements that go back decades (Alvarado et al., Cell 2010;142:568–579; Dawson et al., Structure 2007;15:942–954; Lemmon et al., Embo J 1997;16:281–294; Mattoon et al., Proc Natl Acad Sci USA 2004;101:923–928; Mayawala et al., Febs Lett 2005;579:3043–3047; Ozcan et al., Proc Natl Acad Sci USA 2006;103:5735–5740). This type of asymmetric structure has not been seen for the human EGF receptor family and it may or may not be important for function in that realm. We hypothesize that conformational changes in the Drosophila system have been optimized for the transition, whereas the barrier for the same transition is much higher in the human forms. To address our hypothesis we perform dynamic importance sampling (DIMS) (Perilla et al., J Comput Chem 2010;32:196–209) for barrier crossing transitions in both Drosophila and human EFGRs. For each set of transitions, we work from the hypothesis, based on results from the AdK system, that salt-bridge pairs making and breaking connections are central to the conformational change. To evaluate the effectiveness of the salt-bridges as drivers for the conformational change, we use the effective transfer entropy based on stable state MD calculations (Kamberaj and Der Vaart, Biophys J 2009;97:1747–1755) to define a reduced subset of degrees of freedom that seem to be important for driving the transition (Perilla and Woolf, J Chem Phys 2012;136:164101). Our results suggest that salt-bridge making and breaking is not the dominant factor in driving the symmetric to asymmetric transition, but that instead it is a result of more concerted and correlated functional motions within a subset of the dimer structures. Furthermore, the analysis suggests that the set of residues involved in the transitions from the Drosophila relative to the human forms differs and that this difference in substate distributions relates to why the asymmetric form may be more common to Drosophila than to the human forms. We close with a discussion about the residues that may be changed in the human and the Drosophila forms to potentially shift the kinetics of the symmetric to asymmetric transition.
doi:10.1002/prot.24257
PMCID: PMC3968921  PMID: 23348956
epidermal growth factor receptor; molecular dynamics; conformational change; order parameters; extra-cellular domain
2.  Festschrift in the Honor of Stephen H. White’s 70th Birthday 
The Journal of Membrane Biology  2010;239(1-2):1-3.
The Symposium ‘Frontiers in membrane and membrane protein biophysics: experiments and theory’, held this year at the University of California, Irvine (August 19–20), celebrated the 70th Birthday of Stephen H. White by bringing together distinguished experimentalists and theoreticians to discuss the state of the art and future challenges in the field of membrane and membrane protein biophysics. The meeting and this special issue highlight the highly interdisciplinary nature of membrane and membrane protein biophysics, and the tremendous contributions that S. H. White and his lab have brought to the field.
doi:10.1007/s00232-010-9337-3
PMCID: PMC3030939  PMID: 21191785
S. H. White; Membrane and membrane protein biophysics
3.  From the gating charge response to pore domain movement: Initial motions of Kv1.2 dynamics under physiological voltage changes 
Molecular membrane biology  2009;26(8):397-421.
Recent structures of the potassium channel provide an essential beginning point for explaining how the pore is gated between open and closed conformations by changes in membrane voltage. Yet, the molecular details of this process and the connections to transmembrane gradients are not understood. To begin addressing how changes within a membrane environment lead to the channel’s ability to sense shifts in membrane voltage and to gate, we performed double-bilayer simulations of the Kv1.2 channel. These double-bilayer simulations enable us to simulate realistic voltage drops from resting potential conditions to depolarized conditions by changes in the bath conditions on each side of the bilayer. Our results show how the voltage sensor domain movement responds to differences in transmembrane potential. The initial voltage sensor domain movement, S4 in particular, is modulated by the gating charge response to changes in voltage and is initially stabilized by the lipid headgroups. We show this response is directly coupled to the initial stages of pore domain motion. Results presented here provide a molecular model for how the pre-gating process occurs in sequential steps: Gating charge response, movement and stabilization of the S4 voltage sensor domain, and movement near the base of the S5 region to close the pore domain.
doi:10.3109/09687680903278539
PMCID: PMC2848128  PMID: 19883299
Voltage gating; ionic solution; double-layer effect; S4 domain
4.  The role of Domain:Domain Interactions Vs Domain:Water Interactions in the coarse-grained simulations of the E1P to E2P transitions in Ca-ATPase (SERCA) 
Proteins  2012;80(8):1929-1947.
SERCA is an important model system for understanding the molecular details of conformational change in membrane transport systems. This reflects the large number of solved x-ray structures and the equally large database of mutations that have been assayed. In this computational study we provide a molecular dynamics description of the conformational changes during the E1P -> E2P transitions. This set of states further changes with insertion mutants in the A-M3 linker region. These mutants were experimentally shown to lead to significant shifts in rates between the E1P -> E2P states. Using the population shift framework and dynamic importance sampling method along with coarse-grained representations of the protein, lipid and water, we suggest why these changes are found. The calculations sample on intermediates and suggest that changes in interactions, individual helix interactions and water behavior are key elements in the molecular compositions that underlie shifts in kinetics. In particular, as the insertion length grows, it attracts more water and disrupts domain interactions, creating changes as well at the sites of key helix interactions between the A-Domain and the P-Domain. This provides a conceptual picture that aids understanding of the experimental results.
doi:10.1002/prot.24070
PMCID: PMC3388165  PMID: 22422644
CaATPase; SERCA; conformational transition; SERCA catalytic cycle; molecular dynamics; DIMS; coarse-grained simulation
5.  MDAnalysis: A Toolkit for the Analysis of Molecular Dynamics Simulations 
Journal of computational chemistry  2011;32(10):2319-2327.
MDAnalysis is an object-oriented library for structural and temporal analysis of molecular dynamics (MD) simulation trajectories and individual protein structures. It is written in the Python language with some performance-critical code in C. It uses the powerful NumPy package to expose trajectory data as fast and efficient NumPy arrays. It has been tested on systems of millions of particles. Many common file formats of simulation packages including CHARMM, Gromacs, Amber, and NAMD and the Protein Data Bank format can be read and written. Atoms can be selected with a syntax similar to CHARMM’s powerful selection commands. MDAnalysis enables both novice and experienced programmers to rapidly write their own analytical tools and access data stored in trajectories in an easily accessible manner that facilitates interactive explorative analysis. MDAnalysis has been tested on and works for most Unix-based platforms such as Linux and Mac OS X. It is freely available under the GNU Public License from http://mdanalysis.googlecode.com.
doi:10.1002/jcc.21787
PMCID: PMC3144279  PMID: 21500218
6.  Splaying of Aliphatic Tails Plays a Central Role in Barrier Crossing During Liposome Fusion 
The journal of physical chemistry. B  2010;114(34):11061-11068.
The fusion between two lipid bilayers involves crossing a complicated energy landscape. The limiting barrier in the process appears to be between two closely opposed bilayers, and the intermediate state where the outer leaflets are fused. We have performed molecular dynamics simulations to characterize the free energy barrier for the fusion of two liposomes and to examine the molecular details of barrier crossing. In order to capture the slow dynamics of fusion, a model using coarse-grained representations of lipids was used. The fusion between pairs of liposomes was simulated for four systems: DPPC, DOPC, a 3:1 mixture of DPPC/DPPE and an asymmetric lipid tail system in which one tail of DPPC was reduced to half the length (ASTail). The weighted histogram method was used to compute the free energy as a function of separation distance. The relative barrier heights for these systems was found to be ASTail≫DPPC>DPPC/DPPE>DOPC, in agreement with experimental observations. Further, the free energy curves for all four can be overlayed on a single curve by plotting the free energy versus the surface separation (differing only in the point of fusion). These simulations also confirm that the two main contributions to the free energy barrier are the removal of water between the vesicles and the deformation of the vesicle. The most prominent molecular detail of barrier crossing in all cases examined was the splaying of lipid tails, where a single splayed lipid formed a bridge between the two outer leaflets that promotes additional lipid mixing between the vesicles and eventually leads to fusion. The tail splay appears to be closely connected to the energetics of the process. For example, the high barrier for the ASTail is the result of a smaller distance between terminal methyl groups in the splayed molecule. The shortening of this distance requires the liposomes to be closer together, which significantly increases the cost of water removal and bilayer deformation. Before tail splay can initiate fusion, contact must occur between a tail end and the external water. In isolated vesicles, the contact fraction is correlated to the fusogenicity difference between DPPC and DOPC. Moreover, for planar bilayers the contact fraction is much lower for DPPC, which is consistent with its lack of fusion in giant vesicles. The simulation results show the key roles of lipid tail dynamics in governing the fusion energy landscape.
doi:10.1021/jp1055182
PMCID: PMC2929012  PMID: 20701307
7.  Cooperative Nature of Gating Transitions in K+ Channels as seen from Dynamic Importance Sampling Calculations 
Proteins  2010;78(5):1105-1119.
The growing dataset of K+ channel x-ray structures provides an excellent opportunity to begin a detailed molecular understanding of voltage-dependent gating. These structures, while differing in sequence, represent either a stable open or closed state. However, an understanding of the molecular details of gating will require models for the transitions and experimentally testable predictions for the gating transition. To explore these ideas, we apply Dynamic Importance Sampling (DIMS) to a set of homology models for the molecular conformations of K+ channels for four different sets of sequences and eight different states. In our results, we highlight the importance of particular residues upstream from the PVP region to the gating transition. This supports growing evidence that the PVP region is important for influencing the flexibility of the S6 helix and thus the opening of the gating domain. The results further suggest how gating on the molecular level depends on intra-subunit motions to influence the cooperative behavior of all four subunits of the K+ channel. We hypothesize that the gating process occurs in steps: first sidechain movement, then inter- S5-S6 subunit motions, and lastly the large-scale domain rearrangements.
doi:10.1002/prot.22632
PMCID: PMC2822122  PMID: 19950367
ion-channels; conformational change; transition path sampling; membrane proteins
8.  Zipping and Unzipping of Adenylate Kinase: Atomistic Insights into the Ensemble of Open ↔ Closed Transitions 
Journal of molecular biology  2009;394(1):160-176.
Adenylate kinase (AdK), a phosphotransferase enzyme, plays an important role in cellular energy homeostasis. It undergoes a large conformational change between an open and a closed state, even in the absence of substrate. We investigate the apo-AdK transition at the atomic level both with free energy calculations and our new dynamic importance sampling (DIMS) molecular dynamics (MD) method. DIMS is shown to sample biologically relevant conformations as verified by comparing an ensemble of hundreds of DIMS transitions to AdK crystal structure intermediates. The simulations reveal in atomic detail how hinge regions partially and intermittently unfold during the transition. Conserved salt bridges are seen to have important structural and dynamic roles; in particular four ionic bonds are identified that open in a sequential, zipper-like fashion and thus dominate the free energy landscape of the transition. Transitions between the closed and open conformations only have to overcome moderate free energy barriers. Unexpectedly, the closed and open state encompass broad free energy basins that contain conformations differing in domain hinge motions by up to 40°. The significance of these extended states is discussed in relation to recent experimental FRET measurements. Taken together, these results demonstrate how a small number of cooperative key interactions can shape the overall dynamics of an enzyme and suggest an “all-or-nothing” mechanism for the opening and closing of AdK. Our efficient DIMS-MD computer simulation approach can provide a detailed picture of a functionally important macromolecular transition and thus help to interpret and suggest experiments to probe the conformational landscape of dynamic proteins such as AdK.
doi:10.1016/j.jmb.2009.09.009
PMCID: PMC2803350  PMID: 19751742
adenylate kinase; importance sampling; molecular dynamics; transitions; free energy
9.  How a Small Change in Retinal Leads to G-Protein Activation: Initial Events Suggested by Molecular Dynamics Calculations 
Proteins  2007;66(3):559-574.
Rhodopsin is the prototypical G-protein coupled receptor, coupling light activation with high efficiency to signaling molecules. The dark-state X-ray structures of the protein provide a starting point for consideration of the relaxation from initial light activation to conformational changes that may lead to signaling. In this study we create an energetically unstable retinal in the light activated state and then use molecular dynamics simulations to examine the types of compensation, relaxation, and conformational changes that occur following the cis–trans light activation. The results suggest that changes occur throughout the protein, with changes in the orientation of Helices 5 and 6, a closer interaction between Ala 169 on Helix 4 and retinal, and a shift in the Schiff base counterion that also reflects changes in sidechain interactions with the retinal. Taken together, the simulation is suggestive of the types of changes that lead from local conformational change to light-activated signaling in this prototypical system.
doi:10.1002/prot.21175
PMCID: PMC2848121  PMID: 17109408
membrane protein; simulation; G-protein coupled receptors; rhodopsin; photoisomerization

Results 1-9 (9)