Machine Learning-Assisted Directed Evolution Navigates a Combinatorial Epistatic Fitness Landscape with Minimal Screening Burden

Due to screening limitations, in directed evolution (DE) of proteins it is rarely feasible to fully evaluate combinatorial mutant libraries made by mutagenesis at multiple sites. Instead, DE often involves a single-step greedy optimization in which the mutation in the highest-fitness variant identified in each round of single-site mutagenesis is fixed. However, because the effects of a mutation can depend on the presence or absence of other mutations, the efficiency and effectiveness of a single-step greedy walk is influenced by both the starting variant and the order in which beneficial mutations are identified—the process is path-dependent. We recently demonstrated a path-independent machine learning-assisted approach to directed evolution (MLDE) that allows in silico screening of full combinatorial libraries made by simultaneous saturation mutagenesis, thus explicitly capturing the effects of cooperative mutations and bypassing the path-dependence that can limit greedy optimization. Here, we thoroughly investigate and optimize an MLDE workflow by testing a number of design considerations of the MLDE pipeline. Specifically, we (1) test the effects of different encoding strategies on MLDE efficiency, (2) integrate new models and a training procedure more amenable to protein engineering tasks, and (3) incorporate training set design strategies to avoid information-poor low-fitness protein variants (“holes”) in the training data. When applied to an epistatic, hole-filled, four-site combinatorial fitness landscape of protein G domain B1 (GB1), the resulting focused training MLDE (ftMLDE) protocol achieved the global fitness maximum up to 92% of the time at a total screening burden of 470 variants. In contrast, minimal-screening-burden single-step greedy optimization over the GB1 fitness landscape reached the global maximum just 1.2% of the time; ftMLDE matching this minimal screening burden (80 total variants) achieved the global optimum up to 9.6% of the time with a 49% higher expected maximum fitness achieved. To facilitate further development of MLDE, we present the MLDE software package (https://github.com/fhalab/MLDE), which is designed for use by protein engineers without computational or machine learning expertise.

Towards Bayesian Quantification of Permeability in Micro-scale Porous Structures – The Database of Micro Networks

This article develops a Bayesian framework to quantify the absolute permeability of water in a porous structure from the geometry and clustering parameters of its underlying pore-throat network. These parameters include the network`s diameter, transivity, degree, centrality, assortativity, edge density, K-core decomposition, Kleinberg’s hub centrality scores, Kleinberg's authority centrality scores, length, and porosity. In addition, the incorporated clustering aspects of the networks have been determined with respect to several clustering criteria – edge betweenness, greedy optimization of modularity, multi-level optimization of modularity, and short random walks. As such, the article takes the first footsteps of creating a Database of Micro Networks for micro-scale porous structures, to be used as main input stream for the proposed Bayesian scheme. Doi: 10.28991/HIJ-2020-01-04-02 Full Text: PDF

Optimization Algorithms for Detection of Social Interactions

Community detection is one of the most challenging and interesting problems in many research areas. Being able to detect highly linked communities in a network can lead to many benefits, such as understanding relationships between entities or interactions between biological genes, for instance. Two different immunological algorithms have been designed for this problem, called Opt-IA and Hybrid-IA, respectively. The main difference between the two algorithms is the search strategy and related immunological operators developed: the first carries out a random search together with purely stochastic operators; the last one is instead based on a deterministic Local Search that tries to refine and improve the current solutions discovered. The robustness of Opt-IA and Hybrid-IA has been assessed on several real social networks. These same networks have also been considered for comparing both algorithms with other seven different metaheuristics and the well-known greedy optimization Louvain algorithm. The experimental analysis conducted proves that Opt-IA and Hybrid-IA are reliable optimization methods for community detection, outperforming all compared algorithms.