Improvements to the APBS biomolecular solvation software suite

The Adaptive Poisson-Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomolecular assemblages that has provided impact in the study of a broad range of chemical, biological, and biomedical applications. APBS addresses three key technology challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomolecular solvation and electrostatics, robust and scalable software for applying those theories to biomolecular systems, and mechanisms for sharing and analyzing biomolecular electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this manuscript, we discuss the models and capabilities that have recently been implemented within the APBS software package including: a Poisson-Boltzmann analytical and a semi-analytical solver, an optimized boundary element solver, a geometry-based geometric flow solvation model, a graph theory based algorithm for determining p$K_a$ values, and an improved web-based visualization tool for viewing electrostatics

Computational simulations and methods for biomedical applications

The interplay of molecular simulations and experiment have been instrumental in the last decade in establishing quantitative understanding of the physics underlying molecular processes relevant to applications involving interfaces, polymers and biopolymers and the water solvent used to solvate them. Water in confinement is present in a range of biologi- cal environments on the cellular level, important for stimuli responsive polymers and their use as drug delivery vehicles, and is ubiquitous in many technological applications such as water desalination. In the first half of this dissertation, I have used a range of experimen- tal and simulation techniques to study water in nanoscale confinement for water between graphene sheets and water trapped in stimuli-responsive star diblock polymers. Using MD simulations to study water confined between two graphene walls, it was observed that dif- ferent phases of water could be created as a function of the two-dimensional density and graphene wall flexibility such as square and hexagonal ice. Additionally, at incommensurate 2D densities, the flexible walls were found to bend, creating a coexistence in the system between n- and (n+1) water interlayers. Using small angle X-ray scattering and MD simula- tions, I determined that by varying the hydrophilic block chemistry of the star polymer arms using poly-ethylene glycol (PEG), poly-2,methyl-oxazoline (POXA) and a highly branched polycarbonate-based polymer with a pendant hydrophilic group (PC1), only the PEG sys- tem displayed thermosensitivity over the temperature range observed due to reduction in water entropy, while an increased sidechain length and charge density leads to decreased sol- vent interactions. In addition to temperature sensitivity, pH sensitivity of acidic, basic and neutral polymers was studied in non-degradable nanogel star polymers. Using small angle X-ray scattering, it was found that the acidic (PMAA) and basic (PDMAEMA) polymers exhibited sharp transitions between expanded and collapsed states, with apparent pKas that were qualitatively different from the reported monomer pKas. By modulating the fraction of basic or acidic groups in the hydrophilic region, we were also able to change the apparent pKa of the star polymer.Despite the large success of traditional atomistic simulation methods, their applicability to systems of large size and long time scales are prohibitive. Therefore there exists a need to develop novel methods to overcome this obstacle. In the second half of my thesis I present an efficient method to evaluate the electrostatic interactions in large molecular systems based on the linearized Poisson-Boltzmann equation (LPBE) , which allows for the simulation of much larger systems at a fraction of the cost. I have developed a robust software imple- mentation of the fully analytical LPBE model, PB-AM, which solves for the complete mutual polarization potential of a system comprised of an arbitrary number of molecules with ar- bitrary charge distributions in a screened environment with each molecule represented as a single, spherical, low dielectric cavity. I also developed a software implementation of the semi-analytical LPBE solution, PB-SAM that extends the analytical model that repre- sents a molecule as a collection over overlapping rigid spheres that better describes a detailed molecular boundary. The software is available as stand-alone code, with automated installa- tion using CMake and is also available as a part of the distributed and open source software in the highly popular Adaptive Poisson-Boltzmann Solver (APBS) package. Both software implementations have new features of a simple application programming interface, can pro- duce electrostatic potential visualizations in two and three dimensions, and run Brownian dynamics schemes with a variety of applications

Coexistence of Multilayered Phases of Confined Water: The Importance of Flexible Confining Surfaces

Flexible nanoscale confinement is critical to understanding the role that bending fluctuations play on biological processes where soft interfaces are ubiquitous or to exploit confinement effects in engineered systems where inherently flexible 2D materials are pervasively employed. Here, using molecular dynamics simulations, we compare the phase behavior of water confined between flexible and rigid graphene sheets as a function of the in-plane density, ρ_2D. We find that both cases show commensurate mono-, bi-, and trilayered states; however, the water phase in those states and the transitions between them are qualitatively different for the rigid and flexible cases. The rigid systems exhibit discontinuous transitions between an (<i>n</i>)-layer and an (<i>n</i>+1)-layer state at particular values of ρ_2D, whereas under flexible confinement, the graphene sheets bend to accommodate an (<i>n</i>)-layer and an (<i>n</i>+1)-layer state coexisting in equilibrium at the same density. We show that the flexible walls introduce a very different sequence of ice phases and their phase coexistence with vapor and liquid phases than that observed with rigid walls. We discuss the applicability of these results to real experimental systems to shed light on the role of flexible confinement and its interplay with commensurability effects

Role of hydrophilicity and length of diblock arms for determining star polymer physical properties.

We present a molecular simulation study of star polymers consisting of 16 diblock copolymer arms bound to a small adamantane core by varying both arm length and the outer hydrophilic block when attached to the same hydrophobic block of poly-δ-valerolactone. Here we consider two biocompatible star polymers in which the hydrophilic block is composed of polyethylene glycol (PEG) or polymethyloxazoline (POXA) in addition to a polycarbonate-based polymer with a pendant hydrophilic group (PC1). We find that the different hydrophilic blocks of the star polymers show qualitatively different trends in their interactions with aqueous solvent, orientational time correlation functions, and orientational correlation between pairs of monomers of their polymeric arms in solution, in which we find that the PEG polymers are more thermosensitive compared with the POXA and PC1 star polymers over the physiological temperature range we have investigated

PB-AM: An open-source, fully analytical linear poisson-boltzmann solver.

We present the open source distributed software package Poisson-Boltzmann Analytical Method (PB-AM), a fully analytical solution to the linearized PB equation, for molecules represented as non-overlapping spherical cavities. The PB-AM software package includes the generation of outputs files appropriate for visualization using visual molecular dynamics, a Brownian dynamics scheme that uses periodic boundary conditions to simulate dynamics, the ability to specify docking criteria, and offers two different kinetics schemes to evaluate biomolecular association rate constants. Given that PB-AM defines mutual polarization completely and accurately, it can be refactored as a many-body expansion to explore 2- and 3-body polarization. Additionally, the software has been integrated into the Adaptive Poisson-Boltzmann Solver (APBS) software package to make it more accessible to a larger group of scientists, educators, and students that are more familiar with the APBS framework. © 2016 Wiley Periodicals, Inc

Role of Hydrophilicity and Length of Diblock Arms for Determining Star Polymer Physical Properties

We present a molecular simulation study of star polymers consisting of 16 diblock copolymer arms bound to a small adamantane core by varying both arm length and the outer hydrophilic block when attached to the same hydrophobic block of poly-δ-valerolactone. Here we consider two biocompatible star polymers in which the hydrophilic block is composed of polyethylene glycol (PEG) or polymethyloxazoline (POXA) in addition to a polycarbonate-based polymer with a pendant hydrophilic group (PC1). We find that the different hydrophilic blocks of the star polymers show qualitatively different trends in their interactions with aqueous solvent, orientational time correlation functions, and orientational correlation between pairs of monomers of their polymeric arms in solution, in which we find that the PEG polymers are more thermosensitive compared with the POXA and PC1 star polymers over the physiological temperature range we have investigated

Effect of Hydrophobic Core Topology and Composition on the Structure and Kinetics of Star Polymers: A Molecular Dynamics Study

We present a molecular dynamics study of the effect of core chemistry on star polymer structural and kinetic properties. This work serves to validate the choice of a model adamantane core used in previous simulations to represent larger star polymeric systems in an aqueous environment, as well as to explore how the choice of size and core chemistry using a dendrimer or nanogel core may affect these polymeric nanoparticle systems, particularly with respect to thermosensitivity and solvation properties that are relevant for applications in drug loading and delivery

Insights into the Transport of Aqueous Quaternary Ammonium Cations: A Combined Experimental and Computational Study

This study focuses on understanding the relative effects of ammonium substituent groups (we primarily consider tetramethylammonium, benzyltrimethylammonium, and tetraethylammonium cations) and anion species (OH^–, HCO₃^–, CO₃^2–, Cl^–, and F^–) on ion transport by combining experimental and computational approaches. We characterize transport experimentally using ionic conductivity and self-diffusion coefficients measured from NMR. These experimental results are interpreted using simulation methods to describe the transport of these cations and anions considering the effects of the counterion. It is particularly noteworthy that we directly probe cation and anion diffusion with pulsed gradient stimulated echo NMR and molecular dynamics simulations, corroborating these methods and providing a direct link between atomic-resolution simulations and macroscale experiments. By pairing diffusion measurements and simulations with residence times, we were able to understand the interplay between short-time and long-time dynamics with ionic conductivity. With experiment, we determined that solutions of benzyltrimethylammonium hydroxide have the highest ionic conductivity (0.26 S/cm at 65 °C), which appears to be due to differences for the ions in long-time diffusion and short-time water caging. We also examined the effect of CO₂ on ionic conductivity in ammonium hydroxide solutions. CO₂ readily reacts with OH^– to form HCO^–₃ and is found to lower the solution ionic conductivity by almost 50%