A GA-Simplex Hybrid Algorithm for Global Minimization of Molecular Potential Energy Functions

In this paper we propose a hybrid genetic algorithm for minimizing molecular potential energy functions. Experimental evidence shows that the global minimum of the potential energy of a molecule corresponds to its most stable conformation, which dictates its properties. The search for the global minimum of a potential energy function is very difficult since the number of local minima grows exponentially with molecule size. The proposed approach was successfully applied to two cases: (i) a simplified version of more general molecular potential energy functions in problems with up to 100 degrees of freedom, and (ii) a realistic potential energy function modeling two different molecules.     

Iterative Convex Quadratic Approximation for Global Optimization in Protein Docking

An algorithm for finding an approximate global minimum of a funnel shaped function with many local minima is described. It is applied to compute the minimum energy docking position of a ligand with respect to a protein molecule. The method is based on the iterative use of a convex, general quadratic approximation that underestimates a set of local minima, where the error in the approximation is minimized in the L¹ norm. The quadratic approximation is used to generate a reduced domain, which is assumed to contain the global minimum of the funnel shaped function. Additional local minima are computed in this reduced domain, and an improved approximation is computed. This process is iterated until a convergence tolerance is satisfied. The algorithm has been applied to find the global minimum of the energy function generated by the Docking Mesh Evaluator program. Results for three different protein docking examples are presented. Each of these energy functions has thousands of local minima. Convergence of the algorithm to an approximate global minimum is shown for all three examples.     

Fast Global Optimization of Difficult Lennard-Jones Clusters

The minimization of the potential energy function of Lennard-Jones atomic clusters has attracted much theoretical as well as computational research in recent years. One reason for this is the practical importance of discovering low energy configurations of clusters of atoms, in view of applications and extensions to molecular conformation research; another reason of the success of Lennard Jones minimization in the global optimization literature is the fact that this is an extremely easy-to-state problem, yet it poses enormous difficulties for any unbiased global optimization algorithm.In this paper we propose a computational strategy which allowed us to rediscover most putative global optima known in the literature for clusters of up to 80 atoms and for other larger clusters, including the most difficult cluster conformations. The main feature of the proposed approach is the definition of a special purpose local optimization procedure aimed at enlarging the region of attraction of the best atomic configurations. This effect is attained by performing first an optimization of a modified potential function and using the resulting local optimum as a starting point for local optimization of the Lennard Jones potential.Extensive numerical experimentation is presented and discussed, from which it can be immediately inferred that the approach presented in this paper is extremely efficient when applied to the most challenging cluster conformations. Some attempts have also been carried out on larger clusters, which resulted in the discovery of the difficult optimum for the 102 atom cluster and for the very recently discovered new putative optimum for the 98 atom cluster.     

Equivalent formulations and necessary optimality conditions for the Lennard–Jones problem

The minimization of molecular potential energy functions is one of the most challenging, unsolved nonconvex global optimization problems and plays an important role in the determination of stable states of certain classes of molecular clusters and proteins. In this paper, some equivalent formulations and necessary optimality conditions for the minimization of the Lennard–Jones potential energy function are presented. A new strategy, the code partition algorithm, which is based on a bilevel optimization formulation, is proposed for searching for an extremal Lennard–Jones code. The convergence of the code partition algorithm is proved and some computational results are reported.     

Minimal interatomic distance in Morse clusters

In this paper we derive a lower bound, independent from the number of atoms N, for the minimal interatomic distances between atoms in a cluster whose total energy is modelled by means of the so called Morse potential. A similar result was previously proven for Lennard–Jones clusters but the proof can not be extended to Morse clusters. Besides the theoretical interest, the derivation of this lower bound is important for the definition of efficient procedures for the computation of the total energy of clusters with a large number of atoms.     

Growth of Nanophase Clusters and Potential Energy Minima: Hysteresis, Oscillations, and Phase Transitions

The structures of small Lennard-Jones clusters (local and global minima) in the range n = 30 - 55 atoms are investigated during growth by random atom deposition using Monte Carlo simulations. The cohesive energy, average coordination number, and bond angles are calculated at different temperatures and deposition rates. Deposition conditions which favor thermodynamically stable (global minima) and metastable (local minima) are determined. We have found that the transition from polyicosahedral to quasicrystalline structures during cluster growth exhibits hysteresis at low temperatures. A minimum critical size is required for the evolution of the quasicrystalline family, which is larger than the one predicted by thermodynamics and depends on the temperature and the deposition rate. Oscillations between polyicosahedral and quasicrystalline structures occur at high temperatures in a certain size regime. Implications for the applicability of global optimization techniques to cluster structure determination are also discussed.     

Asynchronously parallel optimization solver for finding multiple minima

We propose and analyze an asynchronously parallel optimization algorithm for finding multiple, high-quality minima of nonlinear optimization problems. Our multistart algorithm considers all previously evaluated points when determining where to start or continue a local optimization run. Theoretical results show that when there are finitely many minima, the algorithm almost surely starts a finite number of local optimization runs and identifies every minimum. The algorithm is applicable to general optimization settings, but our numerical results focus on the case when derivatives are unavailable. In numerical tests, a Python implementation of the algorithm is shown to yield good approximations of many minima (including a global minimum), and this ability is shown to scale well with additional resources. Our implementation’s time to solution is shown also to scale well even when the time to perform the function evaluation is highly variable. An implementation of the algorithm is available in the libEnsemble library at https://github.com/Libensemble/libensemble.     

The application of the genetic algorithm to the minimization of potential energy functions

We adapted the genetic algorithm to minimize the AMBER potential energy function. We describe specific recombination and mutation operators for this task. Next we use our algorithm to locate low energy conformation of three polypeptides (AGAGAGAGA, A9, and [Met]-enkephalin) which are probably the global minimum conformations. Our potential energy minima are –94.71, –98.50, and –48.94 kcal/mol respectively. Next, we applied our algorithm to the 46 amino acid protein crambin and located a non-native conformation which had an AMBER potential energy 150 kcal/mol lower than the native conformation. This is not necessarily the global minimum conformation, but it does illustrate problems with the AMBER potential energy function. We believe this occurred because the AMBER potential energy function does not account for hydration.     

Minimum Inter-Particle Distance at Global Minimizers of Lennard-Jones Clusters

In computer simulations of molecular conformation and protein folding, a significant part of computing time is spent in the evaluation of potential energy functions and force fields. Therefore many algorithms for fast evaluation of potential energy functions and force fields are proposed in the literature. However, most of these algorithms assume that the particles are uniformly distributed in order to guarantee good performance. In this paper, we prove that the minimum inter-particle distance at any global minimizer of Lennard-Jones clusters is bounded away from zero by a positive constant which is independent of the number of particles. As a by-product, we also prove that the global minimum of an n particle Lennard-Jones cluster is bounded between two linear functions. Our first result is useful in the design of fast algorithms for potential function and force field evaluation. Our second result can be used to decide how good a local minimizer is.     

Molecular conformation of n-alkanes using terrain/funneling methods

Understanding molecular conformation is a first step in understanding the waxing (or formation of crystals) of petroleum fuels. In this work, we study the molecular conformation of typical fuel oils modeled as pure n-alkanes. A multi-scale global optimization methodology based on terrain methods and funneling algorithms is used to find minimum energy molecular conformations of united atom n-alkane models for diesel, home heating, and residual fuel oils. The terrain method is used to gather average gradient and average Hessian matrix information at the small length scale while funneling is used to generate conformational changes at the large length scale that drive iterates to a global minimum on the potential energy surface. In addition, the funneling method uses a mixture of average and point-wise derivative information to produce a monotonically decreasing sequence of objective function values and to avoid getting trapped at local minima on the potential energy surface. Computational results clearly show that the calculated united atom molecular conformations are comprised of zigzag structure with considerable wrapping at the ends of the molecule and that planar zigzag conformations usually correspond to saddle points. Furthermore, the numerical results clearly demonstrate that our terrain/funneling approach is robust and fast.     

Efficient Algorithms for Large Scale Global Optimization: Lennard-Jones Clusters

A stochastic global optimization method is applied to the challenging problem of finding the minimum energy conformation of a cluster of identical atoms interacting through the Lennard-Jones potential. The method proposed incorporates within an already existing and quite successful method, monotonic basin hopping, a two-phase local search procedure which is capable of significantly enlarging the basin of attraction of the global optimum. The experiments reported confirm the considerable advantages of this approach, in particular for all those cases which are considered in the literature as the most challenging ones, namely 75, 98, 102 atoms. While being capable of discovering all putative global optima in the range considered, the method proposed improves by more than two orders of magnitude the speed and the percentage of success in finding the global optima of clusters of 75, 98, 102 atoms.     

A quasi-multistart framework for global optimization of expensive functions using response surface models

We present the AQUARS (A QUAsi-multistart Response Surface) framework for finding the global minimum of a computationally expensive black-box function subject to bound constraints. In a traditional multistart approach, the local search method is blind to the trajectories of the previous local searches. Hence, the algorithm might find the same local minima even if the searches are initiated from points that are far apart. In contrast, AQUARS is a novel approach that locates the promising local minima of the objective function by performing local searches near the local minima of a response surface (RS) model of the objective function. It ignores neighborhoods of fully explored local minima of the RS model and it bounces between the best partially explored local minimum and the least explored local minimum of the RS model. We implement two AQUARS algorithms that use a radial basis function model and compare them with alternative global optimization methods on an 8-dimensional watershed model calibration problem and on 18 test problems. The alternatives include EGO, GLOBALm, MLMSRBF (Regis and Shoemaker in INFORMS J Comput 19(4):497–509, 2007), CGRBF-Restart (Regis and Shoemaker in J Global Optim 37(1):113–135 2007), and multi level single linkage (MLSL) coupled with two types of local solvers: SQP and Mesh Adaptive Direct Search (MADS) combined with kriging. The results show that the AQUARS methods generally use fewer function evaluations to identify the global minimum or to reach a target value compared to the alternatives. In particular, they are much better than EGO and MLSL coupled to MADS with kriging on the watershed calibration problem and on 15 of the test problems.     

Docking of Atomic Clusters Through Nonlinear Optimization

The problem of molecular docking is defined as that of finding a minimum energy configuration of a pair of molecular structures (usually consisting of proteins, DNA or RNA fragments). It is often assumed that the two interacting structures can be considered as rigid bodies and that it is of interest to researchers to develop methods which enable to discover the potential binding sites. Many different models have been proposed in the literature for the definition of the potential energy between two molecular structures, most of which contain at least a term (known as Van Der Waals interaction) which accounts for pairwise attraction between atoms, a repulsion term and a term which takes into account electrostatic forces (Coulomb interaction). Some well known models, and in particular those used in rigid docking, are based on the assumption that the only terms which are relevant in the process of docking are pairwise interactions between atoms belonging to the two different parts of the structure. In this paper the problem of finding the lowest energy configuration of a pair of biomolecular structures, considered as rigid bodies, is defined and formulated as a global optimization problem. In terms of dimension of the search space this formulation is not 'high-dimensional', as there are only six degrees of freedom: 3 translation and 3 rotation parameters. However the energy surface of the docking problem is characterized by a huge number of local minima; moreover each function evaluation is quite expensive (interesting structures usually possess a few thousand atoms each). So there is a strong need both of local and of global optimization procedures. In this paper a local optimization technique, based upon standard non linear programming software and a penalized objective function, is introduced and its potential usefulness in the context of global optimization is outlined.     

An Infeasible Point Method for Minimizing the Lennard-Jones Potential

Minimizing the Lennard-Jones potential, the most-studied modelproblem for molecular conformation, is an unconstrained globaloptimization problem with a large number of local minima. In thispaper, the problem is reformulated as an equality constrainednonlinear programming problem with only linear constraints. Thisformulation allows the solution to approached through infeasibleconfigurations, increasing the basin of attraction of the globalsolution. In this way the likelihood of finding a global minimizeris increased. An algorithm for solving this nonlinear program isdiscussed, and results of numerical tests are presented.     

A successive descent algorithm over a system of local minima

A successive descent algorithm over a system of local minima has been developed to find the global minimum of a function of many variables defined on a simply connected compact set. If the number of local minima is finite and a bound on the global minimum is given, the algorithm finds the global minimum in finitely many steps. Test examples are presented. Translated from Prikladnaya Matematika i Informatika, No. 30, pp. 46–54, 2008.     

Challenges of continuous global optimization in molecular structure prediction

The molecular geometry, the three dimensional arrangement of atoms in space, is a major factor determining the properties and reactivity of molecules, biomolecules and macromolecules. Computation of stable molecular conformations can be done by locating minima on the potential energy surface (PES). This is a very challenging global optimization problem because of extremely large numbers of shallow local minima and complicated landscape of PES. This paper illustrates the mathematical and computational challenges on one important instance of the problem, computation of molecular geometry of oligopeptides, and proposes the use of the Extended Cutting Angle Method (ECAM) to solve this problem.     

A Function to Test Methods Applied to Global Minimization of Potential Energy of Molecules

In this paper we develop a function with a functional form similar to general potential energy functions and whose global minimum is known. We prove that the number of local minimizers of this function increases exponentially with the size of the problem, which characterizes the principal difficulty in minimizing molecular potential energy functions. In order to guarantee the global optimality and to show the difficulty in obtaining the global minimum of this function, we propose the utilization of a deterministic algorithm. The algorithm is based on a branch and bound scheme that uses interval analysis techniques to calculate the lower bounds. Computational results for problems with up to 25 degrees of freedom are presented.     

A Hybrid grey wolf optimizer and genetic algorithm for minimizing potential energy function

In this paper, we propose a new hybrid algorithm between the grey wolf optimizer algorithm and the genetic algorithm in order to minimize a simplified model of the energy function of the molecule. We call the proposed algorithm by Hybrid Grey Wolf Optimizer and Genetic Algorithm (HGWOGA). We employ three procedures in the HGWOGA. In the first procedure, we apply the grey wolf optimizer algorithm to balance between the exploration and the exploitation process in the proposed algorithm. In the second procedure, we utilize the dimensionality reduction and the population partitioning processes by dividing the population into sub-populations and using the arithmetical crossover operator in each sub-population in order to increase the diversity of the search in the algorithm. In the last procedure, we apply the genetic mutation operator in the whole population in order to refrain from the premature convergence and trapping in local minima. We implement the proposed algorithm with various molecule size with up to 200 dimensions and compare the proposed algorithm with 8 benchmark algorithms in order to validate its efficiency for solving molecular potential energy function. The numerical experiment results show that the proposed algorithm is a promising, competent, and capable of finding the global minimum or near global minimum of the molecular energy function faster than the other comparative algorithms.     

A Comparison of Global Optimization Methods for the Design of a High-speed Civil Transport

The conceptual design of aircraft often entails a large number of nonlinear constraints that result in a nonconvex feasible design space and multiple local optima. The design of the high-speed civil transport (HSCT) is used as an example of a highly complex conceptual design with 26 design variables and 68 constraints. This paper compares three global optimization techniques on the HSCT problem and two test problems containing thousands of local optima and noise: multistart local optimizations using either sequential quadratic programming (SQP) as implemented in the design optimization tools (DOT) program or Snyman's dynamic search method, and a modified form of Jones' DIRECT global optimization algorithm. SQP is a local optimizer, while Snyman's algorithm is capable of moving through shallow local minima. The modified DIRECT algorithm is a global search method based on Lipschitzian optimization that locates small promising regions of design space and then uses a local optimizer to converge to the optimum. DOT and the dynamic search algorithms proved to be superior for finding a single optimum masked by noise of trigonometric form. The modified DIRECT algorithm was found to be better for locating the global optimum of functions with many widely separated true local optima.     

Local Optimization Method with Global Multidimensional Search

This paper presents a new method for solving global optimization problems. We use a local technique based on the notion of discrete gradients for finding a cone of descent directions and then we use a global cutting angle algorithm for finding global minimum within the intersection of the cone and the feasible region. We present results of numerical experiments with well-known test problems and with the so-called cluster function. These results confirm that the proposed algorithms allows one to find a global minimizer or at least a deep local minimizer of a function with a huge amount of shallow local minima.