Robust Search Methods for Rational Drug Design Applications

The main topic of this thesis is the development of computational search methods that are useful in drug design applications. The emphasis is on exhaustiveness of the search method such that it can guarantee a certain level of geometric accuracy. In particular, the following two problems are addressed: (i) Prediction of binding mode of a drug molecule to a receptor and (ii) prediction of crystal structures of drug molecules. Predicting the binding mode(s) of a drug molecule to a target receptor is pivotal in structure-based rational drug design. In contrast to most approaches to solve this problem, the idea in this work is to analyze the search problem from a computational perspective. By building on top of an existing docking tool, new methods are proposed and relevant computational results are proven. These methods and results are applicable for other place-and-join frameworks as well. A fast approximation scheme for the docking of rigid fragments is described that guarantees certain geometric approximation factors. It is also demonstrated that this can be translated into an energy approximation for simple scoring functions. A polynomial time algorithm is developed for the matching phase of the docked rigid fragments. It is demonstrated that the generic matching problem is NP-hard. At the same time the optimality of the proposed algorithm is proven under certain scoring function conditions. The matching results are also applicable for some of the fragment-based de novo design methods. On the practical side, the proposed method is tested on 829 complexes from the PDB. The results show that the closest predicted pose to the native structure has the average RMS deviation of 1.06 °A. The prediction of crystal structures of small organic molecules has significantly improved over the last two decades. Most of the new developments, since the first blind test held in 1999, have occurred in the lattice energy estimation subproblem. In this work, a new efficient systematic search method that avoids random moves is proposed. It systematically searches through the space of possible crystal structures and conducts search space cuts based on statistics collected from the structural databases. It is demonstrated that the fast search method for rigid molecules can be extended to include flexible molecules as well. Also, the results of some prediction experiments are provided showing that in most cases the systematic search generates a structure with less than 1.0°A RMSD from the experimental crystal structure. The scoring function that has been developed for these experiments is described briefly. It is also demonstrated that with a more accurate lattice energy estimation function, better results can be achieved with the proposed robust search method

Improved Bounds for 3SUM, kk-SUM, and Linear Degeneracy

Given a set of $n$ real numbers, the 3SUM problem is to decide whether there are three of them that sum to zero. Until a recent breakthrough by Gr{\o}nlund and Pettie [FOCS'14], a simple $\Theta(n^2)$-time deterministic algorithm for this problem was conjectured to be optimal. Over the years many algorithmic problems have been shown to be reducible from the 3SUM problem or its variants, including the more generalized forms of the problem, such as $k$-SUM and $k$-variate linear degeneracy testing ($k$-LDT). The conjectured hardness of these problems have become extremely popular for basing conditional lower bounds for numerous algorithmic problems in P. In this paper, we show that the randomized $4$-linear decision tree complexity of 3SUM is $O(n^{3/2})$, and that the randomized $(2k-2)$-linear decision tree complexity of $k$-SUM and $k$-LDT is $O(n^{k/2})$, for any odd $k\ge 3$. These bounds improve (albeit randomized) the corresponding $O(n^{3/2}\sqrt{\log n})$ and $O(n^{k/2}\sqrt{\log n})$ decision tree bounds obtained by Gr{\o}nlund and Pettie. Our technique includes a specialized randomized variant of fractional cascading data structure. Additionally, we give another deterministic algorithm for 3SUM that runs in $O(n^2 \log\log n / \log n )$ time. The latter bound matches a recent independent bound by Freund [Algorithmica 2017], but our algorithm is somewhat simpler, due to a better use of word-RAM model

Faster all-pairs shortest paths via circuit complexity

We present a new randomized method for computing the min-plus product (a.k.a., tropical product) of two $n \times n$ matrices, yielding a faster algorithm for solving the all-pairs shortest path problem (APSP) in dense $n$-node directed graphs with arbitrary edge weights. On the real RAM, where additions and comparisons of reals are unit cost (but all other operations have typical logarithmic cost), the algorithm runs in time $$\frac{n^3}{2^{\Omega(\log n)^{1/2}}}$$ and is correct with high probability. On the word RAM, the algorithm runs in $n^3/2^{\Omega(\log n)^{1/2}} + n^{2+o(1)}\log M$ time for edge weights in $([0,M] \cap {\mathbb Z})\cup\{\infty\}$. Prior algorithms used either $n^3/(\log^c n)$ time for various $c \leq 2$, or $O(M^{\alpha}n^{\beta})$ time for various $\alpha > 0$ and $\beta > 2$. The new algorithm applies a tool from circuit complexity, namely the Razborov-Smolensky polynomials for approximately representing ${\sf AC}^0[p]$ circuits, to efficiently reduce a matrix product over the $(\min,+)$ algebra to a relatively small number of rectangular matrix products over ${\mathbb F}_2$, each of which are computable using a particularly efficient method due to Coppersmith. We also give a deterministic version of the algorithm running in $n^3/2^{\log^{\delta} n}$ time for some $\delta > 0$, which utilizes the Yao-Beigel-Tarui translation of ${\sf AC}^0[m]$ circuits into "nice" depth-two circuits.Comment: 24 pages. Updated version now has slightly faster running time. To appear in ACM Symposium on Theory of Computing (STOC), 201

EXAFS study of amorphous selenium

An overview of synchrotrons and synchrotron radiation is presented, along with the theory and practical considerations behind several types of X-ray spectroscopy. The theory and practical considerations of density functional theory are also given, with direct reference to some specific software packages. Some synchrotron-excited X-ray spectroscopy measurements and density functional theory calculations of selenium and arsenic-doped selenium films are then outlined. The physical structure of crystalline and amorphous selenium and the electronic structure of amorphous selenium are discussed and comparison is made to the experimental results. A weak feature in the conduction band is identified as a "fingerprint" of the degree of crystallization in amorphous selenium from X-ray absorption measurements. Similarly, a weak feature corresponding to lone-pairs in the valence band is identified as a "fingerprint" of the arsenic concentration from X-ray emission measurements. Finally a detailed model of the structure of amorphous selenium is explained, and compared to experiment. This model is tested both by direct calculations and by a reverse Monte Carlo approach. The implications of this model with respect to the structure of amorphous and arsenic-doped amorphous selenium are discussed. Calculations suggest that simply randomizing the arrangement of "perfect" trigonal selenium is unable to reproduce the measurements of amorphous selenium; a moderate variation in the bond angle of "perfect" trigonal selenium is also necessary

All non-trivial variants of 3-LDT are equivalent

The popular 3-SUM conjecture states that there is no strongly subquadratic time algorithm for checking if a given set of integers contains three distinct elements that sum up to zero. A closely related problem is to check if a given set of integers contains distinct $x_1, x_2, x_3$ such that $x_1+x_2=2x_3$. This can be reduced to 3-SUM in almost-linear time, but surprisingly a reverse reduction establishing 3-SUM hardness was not known. We provide such a reduction, thus resolving an open question of Erickson. In fact, we consider a more general problem called 3-LDT parameterized by integer parameters $\alpha_1, \alpha_2, \alpha_3$ and $t$. In this problem, we need to check if a given set of integers contains distinct elements $x_1, x_2, x_3$ such that $\alpha_1 x_1+\alpha_2 x_2 +\alpha_3 x_3 = t$. For some combinations of the parameters, every instance of this problem is a NO-instance or there exists a simple almost-linear time algorithm. We call such variants trivial. We prove that all non-trivial variants of 3-LDT are equivalent under subquadratic reductions. Our main technical contribution is an efficient deterministic procedure based on the famous Behrend's construction that partitions a given set of integers into few subsets that avoid a chosen linear equation

Data Structures Meet Cryptography: 3SUM with Preprocessing

This paper shows several connections between data structure problems and cryptography against preprocessing attacks. Our results span data structure upper bounds, cryptographic applications, and data structure lower bounds, as summarized next. First, we apply Fiat--Naor inversion, a technique with cryptographic origins, to obtain a data structure upper bound. In particular, our technique yields a suite of algorithms with space $S$ and (online) time $T$ for a preprocessing version of the $N$-input 3SUM problem where $S^3\cdot T = \widetilde{O}(N^6)$. This disproves a strong conjecture (Goldstein et al., WADS 2017) that there is no data structure that solves this problem for $S=N^{2-\delta}$ and $T = N^{1-\delta}$ for any constant $\delta>0$. Secondly, we show equivalence between lower bounds for a broad class of (static) data structure problems and one-way functions in the random oracle model that resist a very strong form of preprocessing attack. Concretely, given a random function $F: [N] \to [N]$ (accessed as an oracle) we show how to compile it into a function $G^F: [N^2] \to [N^2]$ which resists $S$-bit preprocessing attacks that run in query time $T$ where $ST=O(N^{2-\varepsilon})$ (assuming a corresponding data structure lower bound on 3SUM). In contrast, a classical result of Hellman tells us that $F$ itself can be more easily inverted, say with $N^{2/3}$-bit preprocessing in $N^{2/3}$ time. We also show that much stronger lower bounds follow from the hardness of kSUM. Our results can be equivalently interpreted as security against adversaries that are very non-uniform, or have large auxiliary input, or as security in the face of a powerfully backdoored random oracle. Thirdly, we give non-adaptive lower bounds for 3SUM and a range of geometric problems which match the best known lower bounds for static data structure problems