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Bounding the electrostatic free energies associated with linear continuum models of molecular solvation
Jaydeep P. Bardhan,1,2,a͒ Matthew G. Knepley,2,3 and Mihai Anitescu3
1 2

Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA Department of Molecular Biophysics and Physiology, Rush University, Chicago, Illinois 60612, USA 3 Mathematics and Computer Science Division, Argonne National Laboratory, Argonne, Illinois 60439, USA

͑Received 20 December 2008; accepted 23 January 2009; published online 11 March 2009͒ The importance of electrostatic interactions in molecular biology has driven extensive research toward the development of accurate and efficient theoretical and computational models. Linear continuum electrostatic theory has been surprisingly successful, but the computational costs associated with solving the associated partial differential equations ͑PDEs͒ preclude the theory’s use in most dynamical simulations. Modern generalized-Born models for electrostatics can reproduce PDE-based calculations to within a few percent and are extremely computationally efficient but do not always faithfully reproduce interactions between chemical groups. Recent work has shown that a boundary-integral-equation formulation of the PDE problem leads naturally to a new approach called boundary-integral-based electrostatics estimation ͑BIBEE͒ to approximate electrostatic interactions. In the present paper, we prove that the BIBEE method can be used to rigorously bound the actual continuum-theory electrostatic free energy. The bounds are validated using a set of more than 600 proteins. Detailed numerical results are presented for structures of the peptide met-enkephalin taken from a molecular-dynamics simulation. These bounds, in combination with our demonstration that the BIBEE methods accurately reproduce pairwise interactions, suggest a new approach toward building a highly accurate yet computationally tractable electrostatic model. © 2009 American Institute of Physics. ͓DOI: 10.1063/1.3081148͔

Electrostatic interactions between biological molecules and the surrounding aqueous solvent play key roles in determining the affinity and specificity with which biomolecules bind one another.1–3 Modeling these solvation interactions remains a theoretical and computational challenge in part due to the long-range character of electrostatic forces and the need to average over many solvent degrees of freedom.4,5 Implicit-solvent models based on linear, continuum electrostatic theory have been proven highly successful at reproducing a range of experimental phenomenon and explicit-solvent simulations.4,6,7 It has been proven difficult, however, to develop rigorous numerical simulation techniques for the associated system of partial differential equations ͑PDEs͒ that are fast enough to be used in dynamical simulations ͑although notable exceptions do exist8͒. Generalized-Born ͑GB͒ models9–11 represent one of the most popular classes of approaches for estimating electrostatic interactions ͑for recent reviews, see Refs. 12–15͒. These methods have in common two key features. First, every solute atom is associated with a parameter called an effective Born radius that measures the magnitude of solvent screening seen by the atom. Second, the interaction energy between atoms is calculated using an interpolation formula, most often the Still equation,9 that recovers the Born expression exactly for a charge’s self-energy and asymptotically approaches a Coulomb interaction for large interatomic disa͒

Electronic mail: jbardhan@alum.mit.edu.

tances. Modern GB methods can reproduce more expensive PDE simulations to within 1% or 2% accuracy16–23 and are fast enough to be employed in dynamical simulations.19,24,25 Despite these successes, however, numerous studies suggest that GB methods sometimes fail to reproduce relevant features of biomolecular energy landscapes or fail to generate electrostatic forces in agreement with forces from continuum-model calculations.16,26–29 The Coulomb-field approximation ͑CFA͒ plays an important role in many GB models. In the CFA, one assumes that an atom’s self-energy contribution to the electrostatic solvation free energy arises from the bare Coulomb field induced by the atom in the solute volume.10 This assumption gives rise to a volume integral, which Ghosh et al. converted to a surface integral using the divergence theorem. They noted the close relationship between the resulting integral and the apparent-surface-charge ͑ASC͒ integral 30–37 The recently introduced boundary-integralequation. based electrostatics estimation ͑BIBEE͒ model for electrostatics takes this relationship as a starting point and exploits it fully to eliminate the need for the nonphysical interpolation inherent to GB models.38 Removing these interpolations allows BIBEE to capture solvent-screened pairwise interactions much more accurately. In earlier work this improved fidelity was demonstrated by comparing the electrostatic reaction-potential matrices generated by BIBEE, GB models, and high-accuracy boundary-element method ͑BEM͒ simulations of the ASC integral equation. The reaction-potential matrix, which maps the explicitly described charge distribu© 2009 American Institute of Physics


130, 104108-1

Downloaded 11 Mar 2009 to Redistribution subject to AIP license or copyright; see http://jcp.aip.org/jcp/copyright.jsp

Two assumptions are made about the boundary ⍀. and Anitescu J. The solvent region is modeled as a homogeneous dielectric with dielectric constant ⑀2 Ͼ ⑀1. ␸R denotes the vector of reaction potentials at the charge locations. so A−1 determines the induced charge at the boundary. see http://jcp. Knepley. the reaction potential induced at a point r in the solute by ␴͑r͒ is ␸ R͑ r ͒ = ͵ ⍀ ␴ ͑ r Ј͒ d 2r Ј . although not necessarily a curvature.1. Inside ⍀. rЈ෈⍀. In addition. II we specify the precise mathematical model of interest and the ASC boundary-integral-equation ͑BIE͒ formulation of the problem.51. ͑6͒ ͑7͒ II. which points outward from the low-dielectric solute into the solvent. The paper concludes with a brief discussion. 130. 104108 ͑2009͒ tions to the induced reaction potentials. First.jsp . 4 ␲ ⑀ 1ʈ r − r Јʈ ͑5͒ In the linear response model. and there are no water-filled cavities inside the solute to be modeled as regions of high dielectric47. The analysis of the present paper focuses on approximations to A.222. there exists only one solute. the integral equation can be written as ˆ D ‫ = ␴ ͒ء‬− ⑀ ˆ ͚ qk ͑I + ⑀ k=1 nc ‫ץ‬ 1 . Chem. The notation W denotes the Cauchy principal value integral43. A is the operator acting on ␴ on the left-hand side of Eq. IV illustrate the bounds’ effectiveness. THEORY A. the ith column of the reaction-potential matrix represents the vector of nc reaction potentials induced at the charge locations by a unit charge at ri. and regularity conditions at infinity complete the needed boundary conditions. L is the product of three operators L = CA−1B . ⌬Ges = 2 1 T =2 q Lq . and a new diagonal approximation BIBEE/LB introduced in this work generates a rigorous LB.45 that is. the boundary ⍀ is assumed to be connected ͑i. W ‫ץ‬ 1 ␴ ͑ r Ј͒ d 2r Ј ⍀ ‫ ץ‬n ͑ r ͒ 4 ␲ ʈ r − r Јʈ = lim ␦→0 ͵ ‫ץ‬ 1 ␴ ͑ r Ј͒ d 2r Ј .39. with nc discrete point charges located inside the solute-solvent boundary ⍀. At the boundary. the right-hand side in Eq. Linear continuum electrostatic model and boundary-integral-equation formulation We consider a single solute molecule in an infinite solvent region. and C represents the integral operator in Eq. j represents the electrostatic potential induced by solvent polarization at ri by a unit charge at r j.e. ‫ ץ‬n ͑ r ͒ 4 ␲ ʈ r − r kʈ ͑1͒ ˆ ͚ qk =−⑀ k=1 nc where the unknown surface charge distribution ␴͑r͒ captures the effects of solvent polarization ˆ= ⑀ ⑀1 − ⑀2 1 2 ͑ ⑀ 1 + ⑀ 2͒ where B maps the nc charges to the normal displacement field at the boundary ͑that is. where the matrix element Li. B. Computational results in Sec.41. ͑8͒ W ‫ץ‬ 1 ␴ ͑ r Ј͒ d 2r Ј ⍀ ‫ ץ‬n ͑ r ͒ 4 ␲ ʈ r − r Јʈ ‫ץ‬ 1 . both the potential and the normal displacement field are continuous.44 The BIBEE method38 approximates electrostatic solvation free energies using diagonal approximations to the operator A.ʈr−rЈʈϾ␦ ‫ ץ‬n ͑ r ͒ 4 ␲ ʈ r − r Јʈ ͑3͒ Denoting the integral operator in Eq. different diagonal approximations lead to different Downloaded 11 Mar 2009 to 18. ͑4͒ can be written as Bq͒. and in this region the Laplace equation governs the potential. and the reaction-potential matrix L maps the charge values to the reaction potentials at the charge locations. the ith charge has value qi and is located at ri. Section III contains proofs that BIBEE approximations can provide upper and LBs for the electrostatic free energy of a given system. offers a more detailed view of methods’ failings and strengths than do the overall electrostatic solvation free energies.48͒.org/jcp/copyright. Phys. which maps the induced charge distribution ␴͑r͒ to ␸R. We demonstrate in the present paper that BIBEE variants can provide mathematically rigorous upper and lower bounds ͑LBs͒ to the true continuum-model free energy ͑that is. Using the BIE formalism and the particular set of nc charge locations. Accordingly.40 This coupled PDE problem can be solved using the BIE ˆ ␴͑r͒ + ⑀ where q is the nc-length vector of charge values. The solute is treated a homogeneous dielectric medium with low dielectric constant ⑀1.46 The Liapunov-smoothness condition is sufficient to ensure that the operator D‫ ء‬is compact. The BIBEE/CFA method provides a rigorous upper bound to the actual free energy of the continuum model. the free energy that would be calculated if the mixed-dielectric problem were solved exactly͒. Redistribution subject to AIP license or copyright.45 Also. We also describe the BIBEE approach to finding approximate solutions to the BIE. ͑5͒. ͑4͒.42 Note that ⑀1 − ⑀2 Ͻ 0. at every point r ෈ ⍀ there exists a tangent plane. the electrostatic potential obeys a Poisson equation.. the electrostatic component of the solvation free energy can be written as 1 T R q ␸ . it is assumed to be Liapunov smooth. In Sec.aip. ‫ ץ‬n ͑ r ͒ 4 ␲ ʈ r − r kʈ ͑4͒ Given the surface charge distribution ␴͑r͒. Diagonal approximations to the boundary-integral equation ͑2͒ and n͑r͒ represents the normal direction at r.33. we show empirically that the BIBEE by preconditioning ͑BIBEE/P͒ method described in earlier work38 generates an effective but not yet proven LB.104108-2 Bardhan. ͑1͒ as D‫ ء‬and the identity operator by I.30.

jsp .222. 2 ͑9͒ As described in earlier work. Redistribution subject to AIP license or copyright. In the first. ͑16͒ ͑17͒ III. ͑17͒. we study a system with the same charge distribution q situated inside the same boundary ⍀. 50͔͒ for solving BIE numerically using the BEM. the energy expression may be written using Eqs. and ͑8͒ as 1 T −1 2 q CA Bq ˆ −1qTBT͑I − 2D‫͒ء‬−TG͑I + ⑀ ˆ D‫͒ء‬−1Bq =⑀ ͑18͒ after making use of the symmetry of G. The BIBEE/CFA method approximates ␴͑r͒ as the direct Coulomb field due to the charges GD‫ = ء‬DG . this implies that it has a square root. For almost boundaries. the normal derivative of the potential at ⍀ ˆ −1Bq.38 The word preconditioning refers to an approach for accelerating the convergence of Krylov-subspace iterative methods ͓such as GMRES ͑Ref. 104108 ͑2009͒ estimated free energies. Liapunov smooth͒ the operators G and D‫ ء‬are compact. The potential at the boundary can can be written as −⑀ then be determined by solving an exterior Neumann problem. 4 ␲ ʈ r − r Јʈ ͑12͒ and it is known that G is self-adjoint and positive definite. For the space of allowable charge distributions. such that G 1/2G 1/2 = G .1. This condition holds when the solute charge distribution produces a uniform normal field at the boundary because the set of uniform fields is in the or1 I + D‫ء‬.51. such a matrix P is a left preconditioner͒. where the dielectric constant is uniform throughout space ͑that is. We define the single-layer potential operator G such that G␺͑r͒ = Concluding the first stage of the proof. The bounds may then be derived easily. the BIBEE/CFA method is closely related to the CFA employed by GB models for electrostatics. The single-layer potential at ⍀ is then CTq = ␸direct͑r͒ = G␺ . Chem.40. ͑10͒ This approximation takes into account not only the field induced by the solute charge distribution but also the strong normal field induced at r by an infinitesimally small disk of ␴͑r͒ immediately surrounding r.104108-3 Bounding electrostatic free energies J. ͑I + ⑀ ͑19͒ ͑20͒ ͵ ␺ ͑ r Ј͒ d 2r Ј .57 In turn. ϫ͑I + ⑀ so that simplifying we have 1 T −1 2 q CA Bq ͑21͒ ˆ −1qTBTG1/2͑I − 2H͒−1͑I + ⑀ ˆ H͒−1G1/2Bq .46 the BIE for which is ˆ −1Bq͒ . To obtain an equivalent expression for CTq.37. there exists a self-adjoint. see http://jcp. Under the assumptions for the connectedness of ⍀ and the support of the charge distribution. ͑18͒ and using the identity G = G1/2G1/2 then give ˆ −1qTBTG1/2͑I − 2H͒−1G−1/2G1/2G1/2G−1/2 ⑀ ˆ H͒−1G1/2Bq . it is valuable to represent A using a decomposition compatible with the approximations.48. ͑14͒ ␴ P = Bq .38 In particular. H = G1/2D‫ء‬G−1/2 . ⑀1 = ⑀2͒. positive definite operator G1/2. we use the space of continuous functions whose support is strictly contained within ⍀. ˆ D‫ = ͒ء‬G−1/2͑I + ⑀ ˆ H ͒ G 1/2 . In the second stage.38.56–58 and therefore we may define a Hermitian operator H that is similar to D‫ء‬.46.49 thogonal range of the operator 2 The BIBEE/P approximation calculates ␴͑r͒ as as can be shown using the Calderon projector.46 The potential operator G. the operator CT ͑which maps the charge distribution to the direct Coulomb potential at the surface͒ is rewritten using basic tools of potential theory and BIE.33. 2 ͑11͒ where ␺͑r͒ is the unknown on ⍀. =⑀ ͑22͒ The two inverse terms commute.g. the resulting expression for the electrostatic solvation free energy is then simplified by exploiting the quasi-Hermiticity of the integral operators. the CFA assumes that the field induced by ␴͑r͒ at r is zero.56.44 Equation ͑13͒ and the properties of G demonstrate that D‫ ء‬is quasi-Hermitian.59 We wish to write this potential not as CTq but in terms of Bq to make the energy expression more symmetric. Finally. For the second stage of the proof. and writing Downloaded 11 Mar 2009 to 18. 130. single-layer operator D. ͑13͒ ͩ ͪ ˆ ⑀ 1 − ␴CFA = Bq .46. =2⑀ We now prove that the BIBEE/CFA and BIBEE/LB approximations bound the electrostatic free energy. that is. the double-layer potential and its transpose D‫ ء‬are related by Substituting Eqs. ͑19͒ and ͑20͒ into Eq. the potential ␸direct͑r͒ = CTq is harmonic in an open set that includes ⍀ and extends out to infinity. all suitably smooth ͑e.51–55 A matrix P is said to be a preconditioner for the BEM system Ax = b if the preconditioned system PAx = Pb can be solved using fewer matrix-vector products ͑more precisely.. ͑1͒. Phys.org/jcp/copyright. ͑ I − 2 D ‫ = ␺ ͒ء‬− 2 ͑ − ⑀ ͑15͒ ͩ ͪ ˆ ⑀ 1 + ␴LB = Bq . In order to analyze the properties of the estimated electrostatic solvation free energy as we introduce different approximations to the operator A. we rewrite the integral operators as ͑I − 2D‫ = ͒ء‬G−1/2͑I − 2H͒G1/2 . From the definition of B. BOUNDS ON THE ELECTROSTATIC FREE ENERGY ˆ −1G͑I − 2D‫͒ء‬−1Bq . we introduce in this paper and define the BIBEE/LB approximation The proof proceeds in two stages.aip.

0 vertices / Å2. Similarly. applying Eq. we note that our results are proved for the operators acting over the infinite dimensional function spaces and not for their approximations obtained by discretization. and sodium and chloride atoms were added to achieve a salt concentration of 0. ͑24͒ to be written as a sum over the modes 1 T −1 −1 −1 2 ˆ −1͑1 − 2␭D ˆ ␭D q CA Bq = ͚ ⑀ i ͒ ͑1 + ⑀ i ͒ xi . 64͒ was used to generate solvent-excluded surfaces with a probe radius of 1. Comparing Figs.51. 65͒ and the CHARMM22 force field66 with the CMAP correction. ͑24͒ is negative when ˆ. ͑30͒ ˆ Ͻ 0. However.48.aip. ͑27͒ is negative and Because ⑀ ͩ ͪ 1− ˆ ⑀ ˆ ␭D Ն ͑1 + ⑀ i ͒ ∀ i. As expected on physical grounds. III. 1 ˆ͉ Ͻ 2 ͉⑀ and 43. see http://jcp.4 Å. doubling the vertex density to 10 vertices / Å2 did not materially affect the results. and atomic radii and charges were taken from the 66 CHARMM22 parameter set.e. ͑28͒ 1 T −1 −1 −1 2 ˆ −1 ͚ ͑1 − 2␭D q CÂ P Bq = ⑀ i ͒ ͑1͒ xi . We did not prove that BIBEE/P bounds the free energy in the general case.46 the eigenvalues of D lie in the interval the product −1 ˆ ␭ i͒ ͑ 1 − 2 ␭ i͒ ͑ 1 + ⑀ −1 ͑25͒ is positive whenever ⑀1 is finite ͑i. ͑30͒ to obtain that BIBEE/LB gives a LB for the true free energy. Planar-element discretizations of surfaces were generated using previously described techniques. The peptide met-enkephalin ͑AcYGGFMNH2͒ was constructed in an extended conformation using CHARMM ͑Ref. .jsp . This enables Eq. ⑀2 = 80.68 The VMD software package69 was used to solvate the peptide such that no peptide atom was within 8 Å of the edge of the solvent box. we finally have 1 T −1 2 q CA Bq ˆ −1qTBTG1/2VH͑I − 2⌳D͒−1 =⑀ T 1/2 ˆ ⌳D͒−1VH ϫ͑I + ⑀ G Bq . A. 2 . . particle-mesh Ewald electrostatics. For surfaces such as spheres and prolate spheroids. Owing to the difference in scale between the BIBEE/LB estimates and the estimates from the other methods. . BIBEE/CFA. 104108 ͑2009͒ T H = V H⌳ DV H . One of the peptide structures was analyzed in more detail with the reaction-potential matrices calculated using Downloaded 11 Mar 2009 to 18. the program MSMS ͑Ref. it seems to offer an effective bound much closer to the actual free energy than the BIBEE/LB. and Anitescu J. Phys. consistency of the approximation indicates that the bounds we obtained will be satisfied for sufficiently accurate discretizations. the BIBEE methods.org/jcp/copyright. 130. and surface-GB ͑SGB͒/CFA ͑the SGB method of Ghosh et al.145 M. ͑23͒ where ⌳D is the eigenvalue matrix of the operator D‫ء‬.63 For all simulations. Redistribution subject to AIP license or copyright. define the vector T 1/2 G Bq x = VH ͑26͒ Computational results in this section validate the bounds presented in Sec. + 1 / 2͒. ͑31͒ to the BIBEE/CFA approximation of Eq. 2 i ͑27͒ The BIBEE approximations to A generate the approximate free energies 1 T −1 2 q CÂCFABq −1 ˆ −1 ͚ ͑1 − 2␭D =⑀ 1− i ͒ i ͩ ͪ ˆ ⑀ 2 −1 x2 i. Figures 1͑a͒ and 1͑b͒ are time-series plots of the computed electrostatic free energies and Fig. ͑29͒ that the BIBEE/P approximation provides a rigorous LB. BIBEE/P. Knepley.62 it is straightforward to show using Eq. Nonetheless. the symmetric quadratic expression in Eq. because ͩ ͪ 1+ ˆ ⑀ ˆ ␭D Յ ͑1 + ⑀ i ͒ ∀ i.60͒. IV. and 2 fs time steps with snapshots of the trajectory saved every 2500 time steps.1. 2 ͑32͒ we can apply Eq. This bound becomes worse as the ratio ⑀2 / ⑀1 increases and approaches the BIBEE/P bound as the dielectric ratio approaches one ͑data not shown͒.19 BEM. ⑀1 Ͻ ⑀2 and positive when ⑀2 Ͻ ⑀1 due to the the sign of ⑀ To obtain the BIBEE bounds. ͑32͒ to the BIBEE/LB approximation in Eq. For these simulations. the BIBEE/LB results are shown on a separate plot. SGB/CFA. IV.67. Furthermore. and GBMV energies against the BEM simulations. it is immediately evident that the BIBEE/LB method provides a very loose LB to the true free energy. when the integral equation is well posed49. Dynamics were performed in the NPT ensemble at 1 atm pressure using Langevin dynamics. 2 i ˆ 1 T −1 ⑀ −1 ˆ −1 ͚ ͑1 − 2␭D 1+ q CÂLBBq = ⑀ i ͒ 2 2 i ͑29͒ −1 ͩ ͪ x2 i. ͑24͒ Finally.. Met-enkephalin with components xi.222. ͑28͒ gives an approximate free energy that is an upper bound to the true free energy in the continuum model. 70͒ was then performed following 1000 steps of energy minimization and 100 ps of equilibration at 300 K. which possess operators D‫ ء‬with only nonpositive eigenvalues. but lacking the empirical correction terms presented in their work71͒.61. as we demonstrate in Sec. The surface discretizations were computed in MSMS such that the density of vertices was 5. ⑀1 = 1. 2 is a scatter plot of the BIBEE/LB. 2 ͑31͒ Therefore. Electrostatic solvation free energies of the 50 peptide structures were then estimated using Generalized Born with Molecular Volume ͑GBMV͒. Chem. even when one does not know a priori whether D‫ ء‬has positive eigenvalues. i = 1 . 1͑a͒ and 1͑b͒. A molecular dynamics ͑MD͒ simulation of 500 ps in NAMD ͑Ref.. examples demonstrate that the BIBEE/P method provides an effective LB for the free energies when simulating typical molecular surfaces and charge distributions. every term in Eq. RESULTS Because ͓−1 / 2 .104108-4 Bardhan.

and BIBEE/P eigenvectors onto the eigenvectors of the BEM reaction-potential matrix. BIBEE/CFA. 1. As noted previously. ͑a͒ All estimates are plotted. the ͑i . see http://jcp. and SGB/CFA methods. Figs.38 It is important that methods for estimating electrostatic interactions calculate not only an accurate total free energy but also preserve the energetics of interaction between chemical groups. The SGB/CFA eigenvalues are slightly more accurate than the BIBEE/CFA eigenvalues for the dominant eigenmodes but less accurate for the smaller eigenmodes. Phys.1.104108-5 0 −1000 Electrostatic Free Energy (kcal/mol) −2000 −3000 −4000 −5000 −6000 −7000 100 Bounding electrostatic free energies −20 −40 Electrostatic Free Energy (kcal/mol) −60 −80 −100 −120 −140 BEM BIBEE/LB 200 300 Time (ps) 400 500 600 −160 100 BEM SGB/CFA GBMV BIBEE/CFA BIBEE/P 200 300 J. perfect preservation of the pairwise interactions would give rise to a diagonal matrix with diagonal entries of unit magnitude. snapshots have been taken at 10-ps intervals. ͑Color online͒ Comparison of electrostatic solvation free energies using met-enkephalin structures taken from a 500-ps MD simulation plotted as time series. Redistribution subject to AIP license or copyright. Energies are in kcal/mol. the various BIBEE methods give rise to essentially identical eigenvectors ͑data not shown͒. BIBEE/CFA is most accurate for the largestmagnitude eigenvalues and the BIBEE/P method offers the best fidelity to BEM for the smallest eigenvalues. 130. The degree to which the approximate-method eigenvectors align with the actual eigenvectors can then be assessed visually using a heat map. which is expected given that the diagonal ap10 4 10 3 BEM SGB/CFA GBMV BIBEE/CFA BIBEE/P Eigenvalue Magnitude −85 −80 −75 −70 −65 Electrostatic Free Energy from BEM (kcal/mol) −60 −40 −50 −60 −70 −80 −90 −100 −90 10 2 10 1 10 0 10 −1 10 −2 0 10 20 30 40 50 Eigenvalue Index 60 70 80 FIG. To analyze how different methods preserve pairwise interactions with respect to the BEM calculations. GBMV. BEM.38 We believe that discrepancies between the BIBEE and BEM eigenvectors may be a result of discretizing the integral equation for simulation using BEM. 104108 ͑2009͒ Time (ps) 400 500 600 (a) (b) FIG.org/jcp/copyright. Energies are in kcal/mol. Figure 3͑a͒ is a plot of the eigenvalues of the calculated matrices. ͑b͒ BIBEE/LB has been omitted for clarity. BIBEE/CFA.222. SGB/CFA. the off-diagonal entries are nonzero. 4–6 are plots of the projections of the SGB/CFA. we project the eigenvectors of the approximate reactionpotential matrices onto the eigenvectors of the reactionpotential matrix from BEM.51. ͑Color online͒ Comparison of estimated electrostatic solvation free energies using met-enkephalin structures taken from a 500-ps MD simulation plotted as a scatter plot against energies calculated using BEM.72 However. GBMV. Conversely. 2. Of the four electrostatic approximations. ͑Color͒ Eigenvalues of the reaction-potential matrices computed from the final met-enkephalin structure using BEM. j͒ entry of the matrix 0 Estimated Electrostatic Free Energy (kcal/mol) −10 −20 −30 y=x SGB/CFA GBMV BIBEE/CFA BIBEE/P T VSGB/CFA VBEM ͑33͒ represents the projection of the jth eigenvector of the SGB/ CFA reaction-potential matrix onto the jth eigenvector of the BEM reaction-potential matrix. if a method imperfectly reproduces pairwise interactions.aip. BIBEE/P. FIG.jsp . and BIBEE/P. Downloaded 11 Mar 2009 to 18. the GBMV method appears to provide the most accurate eigenvalue estimates. GBMV. In this projection framework. For example. Chem. 3.

The color of cell i. Left axis ͑dashed-dotted line͒: magnitude of the projection of the solute charge vector q onto the corresponding eigenmode. FIG.104108-6 80 70 60 BEM Eigenvalue Index 50 40 30 20 10 Bardhan. the projection of q onto the BEM eigenvectors.1. especially for modes 35-50. however. j represents the projection of the jth eigenvector of the SGB/CFA reaction-potential matrix onto the ith eigenvector of the BEM reaction-potential matrix. The SGB/CFA reactionpotential matrix captures the first 30 eigenmodes slightly more accurately than the BIBEE approximations. However. both GB methods exhibit poor alignment for smaller-magnitude eigenvalues.15 To reconcile these results. show very good alignment throughout the spectrum. Right axis ͑solid line͒: the cumulative electrostatic solvation free energy beginning with the contributions from the dominant eigenmodes. although not always as accurate for estimating total energies. and Anitescu 80 70 60 50 40 30 20 10 10 20 30 40 50 60 SGB/CFA Eigenvalue Index 70 80 J. 104108 ͑2009͒ 10 20 30 40 50 60 70 80 FIG. Redistribution subject to AIP license or copyright.51.jsp Cumulative Electrostatic Free Energy (kcal/mol) Magnitude of Projection Onto Vpb . ͑Color͒ Comparison of the eigenvectors of the BIBEE/P reactionpotential matrix with the eigenvectors from BEM computed from the final met-enkephalin structure. proximations to the integral operator differ only by a multiple of the identity matrix. see http://jcp. The BIBEE methods. which are not approximated as well. ͑Color͒ Comparison of the eigenvectors of the GBMV reactionpotential matrix with the eigenvectors from BEM computed from the final met-enkephalin structure. These modes contribute more to the total electrostatic free energy of solvation than the modes associated with smaller eigenvalues. Downloaded 11 Mar 2009 to 18. 4. Compared to the eigenvectors from SGB/CFA. 5.org/jcp/copyright. The discrepancies between the GBMV and BEM eigenvectors stand in contrast to the good agreement between the GBMV and BEM eigenvalues ͑Fig. 6.222. It appears that GB methods based on the CFA achieve good accuracy by finding good approximations to the dominant eigenvalues and eigenvectors. Knepley.aip. FIG. Chem. Phys. ͑Color͒ Comparison of the eigenvectors of the SGB/CFA reactionpotential matrix with the eigenvectors from BEM computed from the final met-enkephalin structure. it is necessary 80 70 60 BEM Eigenvalue Index 50 40 30 20 10 to understand the relationship between the eigenvectors of the reaction-potential matrix and the charge vector q. and we are investigating possible reasons for these systematic deviations. Energies are in kcal/mol. Approximately one third of the total electro2 0 1 −50 0 0 10 20 30 40 50 60 Eigenvalue Index 70 80 90 −100 10 20 30 40 50 GBMV Eigenvalue Index 60 70 80 FIG. 3͒ and the high accuracy of modern GB methods in reproducing Poisson–Boltzmann ͑PB͒ calculations. 7. and the remaining modes are modeled significantly more accurately using BIBEE. and the cumulative electrostatic free energy obtained as one sums the individual mode contributions beginning with the largest-magnitude eigenvalues. the GBMV eigenvectors are clearly better aligned with the BEM eigenvectors. 130. Not all of the modes important to the solvation free energy are captured. ͑Color online͒ The contribution of different eigenmodes to the total electrostatic solvation free energy computed from the final met-enkephalin structure. Figure 7 is a superposition of two plots. It is interesting that all three methods suffer from some loss of accuracy for modes 20-35.

we have estimated the electrostatic free energy of solvation for the proteins in this data set. however. The results illustrate that the BIBEE/CFA bound holds as proven and that the BIBEE/P method seems to provide a LB in practice. we present instead the application of one of the simplest possible schemes.104108-7 0 Electrostatic Free Energy from BIBEE (kcal/mol) −500 −1000 −1500 −2000 −2500 −3000 −3500 −4000 −4500 −5000 −5000 Bounding electrostatic free energies J. In these simulations. The GBMV method captures the first 50 modes reasonably well. in which weights ␣CFA and ␣ P are found empirically such that the weighted sum ␣CFAECFA + ␣ PE p is approximately equal to the BEM-calculated free energy EBEM.51. Interpolating between the BIBEE/CFA and BIBEE/P estimates −4000 −3000 −2000 −1000 Electrostatic Free Energy from BEM (kcal/mol) 0 FIG. Chem. and this is reflected in the improved accuracy of GBMV with respect to the BEM calculations.jsp .73 and the dielectric constants were ⑀1 = 4 and ⑀2 = 80. The weighting has been selected so that interpolation applied to the the first snapshot gives the BEM-calculated electrostatic free energy. Figures 9͑a͒ and 9͑b͒ plot the interpolated BIBEE free energy calculated using weights determined by forcing the interpolated free energy of the first snapshot to match the free energy from BEM simulation of the first snapshot. For every BEM calculation. 130. In this section. ͑Color online͒ Interpolation between BIBEE/CFA and BIBEE/P to estimate electrostatic solvation free energies of met-enkephalin structures taken from a 500-ps molecular-dynamics simulation. Unfortunately. Protein test suite Feig and Brooks. with an ideal scheme possessing strong mathematical and physical foundations. from the BIBEE/CFA method. even though its bounding properties are unproven. and a corresponding red point from the BIBEE/P approximation directly beneath. we have not yet been able to devise such a theoretically satisfactory solution. The correlation between the BEM and interpolated BIBEE free energies is remarkable. ͑b͒ Energies plotted as a scatter plot against the BEM calculations. ͑Color online͒ Electrostatic solvation free energies calculated using BEM and the free energy bounds estimated using BIBEE/CFA and BIBEE/P using protein geometries employed by Feig and Brooks ͑Ref. ͑a͒ Energies plotted as time series. 15͒. B. C. assembled and prepared a test set of over 600 protein geometries and have made the data available for download. there exists one blue point above the y = x line. Figure 8 is a scatter plot of the free energy bounds against −20 The existence of both upper and LBs for the electrostatic free energy immediately suggests the possibility that one might find an inexpensive interpolation between the bounds to provide a close estimate for the actual free energy.org/jcp/copyright. 104108 ͑2009͒ y=x BIBEE/CFA BIBEE/P the calculated BEM free energies. Redistribution subject to AIP license or copyright. Energies are in kcal/mol. atomic radii and charges were taken from the PARSE parameter set. see http://jcp. 9.222. Because ECFA and E P bound EBEM it is clear that 0 Յ ␣CFA. Energies are in kcal/mol. ␣ P Յ 1. static solvation free energy arises from these modes that correspond to smaller eigenvalues.aip. We wish to emphasize.1. Phys. the purely em0 Estimated Electrostatic Free Energy (kcal/mol) −10 −20 −30 −40 −50 −60 −70 −80 −90 −100 −90 −85 −80 −75 −70 −65 Electrostatic Free Energy from BEM (kcal/mol) −60 y=x SGB/CFA GBMV BIBEE/CFA BIBEE/P Interpolated BIBEE −40 Electrostatic Free Energy (kcal/mol) −60 −80 −100 −120 −140 BEM SGB/CFA GBMV BIBEE/CFA BIBEE/P Interpolated BIBEE 200 300 Time (ps) 400 500 600 −160 100 (a) (b) FIG. weights could be determined from an initial structure or from the mean of a set of representative structures. For calculations in which the free energies of different conformations of the same molecule are of interest. 8. To demonstrate the performance of the BIBEE/CFA and BIBEE/P bounds over a broad range of molecular sizes and shapes. The ensemble of met-enkephalin snapshots provides an illustration.15 in their analysis of modern GB electrostatic models and the models’ accuracy relative to solutions of the PB equation. snapshots have been taken at 10-ps intervals. Downloaded 11 Mar 2009 to 18.

All energies are in kcal/mol.1 0 −3000 J. the provable LB from BIBEE/LB is so loose that it is likely to be of minimal practical value.aip. 10. In particular. 15͒.2 0. Current work therefore focuses on identi- Downloaded 11 Mar 2009 to 18. The fact that the metenkephalin weights used to generate the results in Fig. Lower and upper electrostatic free-energy bounds can be proven rigorously using BIBEE. In contrast.6 0.104108-8 0 Electrostatic Free Energy from BIBEE (kcal/mol) −100 −200 −300 −400 −500 −600 −700 −800 −900 −1000 −1000 Bardhan.51.5 0.4 0. In previous work38 it was shown that the BIBEE methods are typically 2–3 times slower than SGB/CFA methods if one uses the same surface discretization to evaluate the reaction-potential matrices explicitly and approximately ten times faster than BEM simulations based on compressing the dense matrices that represent the discretized integral operators. 48͔͒. in order for the BIBEE bounds to be valuable in practice.jsp . The mean of these weights can then be used generally for proteins.8 y=x BIBEE/CFA BIBEE/P Interpolated BIBEE (Met weight) Interpolated BIBEE (mean Feig weight) 0. It is clear that interpolated free energies calculated using these weights deviate systematically from the BEM-calculated free energies. 130. Knepley. The first set of weights consists of the exact met-enkephalin weights. The bounds appear to hold when the integral equation is discretized and approximated numerically using standard BEM techniques.. Clearly. DISCUSSION In the present paper. ͑b͒ The exact weights for the BIBEE/P approximation plotted against the electrostatic free energies calculated using BEM. ͑Color online͒ Interpolation between BIBEE/CFA and BIBEE/P to estimate the electrostatic solvation free energies of the protein geometries of Feig and Brooks ͑Ref. The BIBEE bounds are derived from diagonal approximations to a BIE formulation of the mixed-dielectric Poisson problem using quasi-Hermitian operator theory58 to characterize the relationship between the approximate free energies and the approximation to the boundary-integral operator. 10͑a͒ is determined by calculating for each protein separately the weights that would cause the interpolated BIBEE free energy to match the BEM calculation. 10͑b͒ is a scatter plot of the exact BIBEE/P weights against the electrostatic free energy calculated using BEM.15 In Fig. The range of the exact weights in this test set suggests that it may be difficult to develop and justify empirical approaches to interpolating between the BIBEE approximations. ͑a͒ Free energies interpolated using either the exact weighting for the first met-enkephalin snapshot ͑such that the interpolated free energy matches the BEM calculation exactly͒ or the mean of the exact weights over all the proteins in the test set of Feig.1. Structures of met-enkephalin taken from a MD simulation have been used to demonstrate the bound performance relative to high-resolution BEM simulations and to GB calculations. 9 are not necessarily suitable for all proteins becomes clear upon using the met-enkephalin weights to interpolate the BIBEE/ CFA and BIBEE/P free energies for the proteins of the test set of Feig and Brooks. We have also employed a set of several hundred protein structures15 to illustrate that the effective ͑but unproven͒ bound from the BIBEE/P approximation holds in practice over a variety of macromolecular geometries. Chem. see http://jcp. 10͑a͒ are plotted BIBEEestimated free energies that have been interpolated using two different sets of weights. The computational complexity of BIBEE calculations therefore merits discussion. in which the electrostatic free energies of a large number of very similar geometries are to be estimated. It is not surprising that this set of interpolated free energies correlates better with BEM calculations than do the free energies from the met-enkephalin weights.55 or FFTSVD ͑Ref. and Anitescu 0. fast multipole53. Phys. 104108 ͑2009͒ −800 −600 −400 −200 Electrostatic Free Energy from BEM (kcal/mol) 0 (EBEM − ECFA) / (EP − ECFA) −2500 −2000 −1500 −1000 −500 Electrostatic Free Energy from BEM (kcal/mol) 0 (a) (b) FIG. pirical nature of the interpolation. Redistribution subject to AIP license or copyright. however.48 This order-of-magnitude improvement is likely only a weak LB because the BIBEE implementation has not been optimized for performance. but its bounding properties remain unproven. the effective bound generated by BIBEE/P might well be valuable. Fig. Both the BEM and BIBEE calculations scale essentially linear with the surface area of the macromolecule if one uses appropriate computational techniques ͓e. it is necessary that they be computable in much less time than is required for full solution of the mixed-dielectric Poisson problem.g.7 0. although more detailed numerical analysis is warranted. we have described how the BIBEE approach to approximating electrostatic interactions can be used to rigorously bound the true electrostatic free energy of interaction between a molecular solute and the surrounding solvent.222. V. The second set of weights used to calculate interpolatedBIBEE energies in Fig. we expect significant further improvements to arise in applications similar to the met-enkephalin calculations in the present work.org/jcp/copyright.3 0.

157. Phys. Russell. Chem. BIBEE in its present form may still be useful for calculations in which continuity of forces is not a requirement. Honig.75 can violate the Liapunov-smoothness criterion in many places on the boundary. G.53 ACKNOWLEDGMENTS The authors thank B. Phys. if obtained. It is not clear whether BIBEE can be adapted to provide forces for dynamics. G.94 would allow new approaches to simulating ionic or protein solutions with many low-dielectric bodies. P. similar to grid-based GB methods. C. The analysis of the BIBEE approximations rests on the compactness of the normal electric-field operator. or that the corrections developed in GB could be used to improve BIBEE eigenvalue estimates. Chem. U.88 The comparison of BIBEE calculations to explicit-solvent simulations is an interesting question for future work. Biophys. and W. 5 B. 7 M. Fine.90 The existence of reasonable upper and LBs has implications for molecular design as well. However. Our results may also have implications for optimization of electrostatic interactions between molecules. K. J. Biophys. Honig and A.76–79 It is possible that algorithms introduced recently to define excluded volumes in the GB model80 will be preferable to the standard surfaces. Sharp and B.82 may also be a suitable starting point.P. In particular. Rashin. It is clear that methods for estimating electrostatic interactions must reproduce both the eigenvalues and the eigenvectors of the reaction-potential matrices of high-resolution simulations of the linear-continuum model if such methods are to be described as accurate. 23. particularly branch-and-bound pruning algorithms and hierarchical search techniques. Chem. Warwicker and H.9–11. C. and Computational Sciences Division Subprogram of the Office of Advanced Scientific Computing Research.23.1. J. and M. but only the ones corresponding to eigenvectors that realistic charge distributions can excite. including the van der Waals surface. It is also possible that the combination of BIEs and quasi-Hermitian theory may yield further insights into BIBEE/P or the precise relationship between the eigenvectors of the true and BIBEE-approximated reaction-potential matrices. The bounds derived in the present work suggest that it is possible to find accurate eigenvalue estimates using BIBEE. see http://jcp. Kirkwood. It is possible that the BIBEE method may be useful for the development of further refinements of GB methods. Kirkwood. 9 W. Shenkin. P. 6 J. IV of this paper. Nicholls. The derived bounds do not demonstrate that the actual reaction-potential-matrix eigenvalues are bounded by the eigenvalues from the BIBEE reaction-potential matrices.21. A 1 2 Downloaded 11 Mar 2009 to 18. Rev. Still. 503 ͑1985͒. Tanford and J. which raises the possibility that the BIBEE bounds presented here may be used to bound the desolvation-matrix eigenvalues. Still.18. gratefully acknowledges support from a Wilkinson Fellowship in Scientific Computing. do not excite the modes that BIBEE/P would mispredict. Information.222. David. and the solvent-excluded ͑also known as molecular͒ surface. 2. A.81. C. R. one subject for future work on BIBEE is incorporating algorithms that generate suitably smooth surfaces.aip. However. 301 ͑1990͒. Biophys.92 The desolvation matrix associated with rigid molecular binding is a difference of reaction-potential matrices. Watson. This work was supported by the Mathematical. Annu. The rigorous alpha-shapes method developed by Liang et al. S. extending the proof for the BIBEE bounds to disconnected dielectric boundaries93. 17. in part. we emphasize that bounding the electrostatic free energy does not necessarily require bounding all the eigenvalues.62 charge distributions that “excite” these eigenstates would have their responses mispredicted by the BIBEE/P method.51. Soc. it should be emphasized that BIBEE achieves its level of accuracy without any empirical fitting terms and without any parametrization beyond what is required for the continuum model itself. 79. Science 268. Chem. Such a proof would require that the BIBEE methods give rise to reaction-potential matrices with the same eigenvectors as the true reaction-potential matrix. the present work demonstrates that for a given charge distribution. J. L. 130. DE-AC0206CH11357. as indicated by the excellent alignment between the eigenvectors of the BEM and BIBEE reaction-potential matrices. Chem. Instead.20. Rev. and we acknowledge that the presented BIBEE methods do not provide eigenvalue approximations of uniformly high quality as does the GBMV approach. Mol. Hendrickson. F. The BIBEE approach thus satisfies one of the necessary conditions for a satisfactory implicit-solvent model. as GB has been adapted. Finally.jsp . Such bounds. It is possible that point-charge-based charge distributions. Because it is known that some simple surfaces do in fact have positive eigenvalues. 19.org/jcp/copyright. the solvent-accessible surface. 3 A. 1144 ͑1995͒. Luo. C. Department of Energy under Contract No. Chem. J.71. As shown in earlier work38 and in Sec. BIBEE methods reproduce with high fidelity component-wise interactions.74. 351 ͑1934͒. Current work is directed toward developing methods for inexpensively estimating these eigenvalues. Compactness depends. and T. Biol.61. Chem. Honig. F. Office of Science.89 However. 4 K. Comput. J. could be useful for screening candidate ligand geometries in molecular design. 5333 ͑1957͒.91.83–87 and many GB models have been presented in combination with physical interpretations drawn from the continuum model or using parameters fit against continuum calculations. Hawley. 10 D.B. and B. on smoothness properties of the solutesolvent boundary. The BIBEE bounds themselves may be useful for Monte Carlo simulations of macromolecules. Gilson. 6127 ͑1990͒. 184. Gilson. Redistribution subject to AIP license or copyright. K.S. Phys. 8 R. Tempczyk. J. Roux for the use of CHARMM. T. Although the bounds appear to still hold for the molecular surfaces employed here. Am. 283 ͑1984͒.10. 671 ͑1982͒. A. 104108 ͑2009͒ fying why the BIBEE/P method works in practice to generate LBs for electrostatic free energies when considering molecular charge distributions and surfaces. C. Warshel and S. J. Mol.104108-9 Bounding electrostatic free energies J. Qiu. the availability of rapidly calculable bounds makes it possible to accelerate sampling by avoiding expensive electrostatics simulations. R. which rarely have charges within an atomic radius of the dielectric boundary. Am. J. Many of the most popular definitions. Hollinger. Q. J. A. the BIBEE methods generate upper and LBs for the true electrostatic solvation free energy. Biol. 112. 1244 ͑2002͒. Soc. Explicitsolvent MD simulations represent another model against which GB calculations can be assessed.

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